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Indian Journal of Medical Microbiology, Vol. 30, No. 1, January-March, 2012, pp. 6-15 Review Article Human immunodeficiency virus type-2-A milder, kinder virus: An update R Kannangai1, S David1, G Sridharan2 1 Department of Clinical Virology, Christian Medical College, Vellore - 632 055, India Correspondence Address: Date of Acceptance: 17-Oct-2011 Code Number: mb12003 PMID: 22361754 DOI: 10.4103/0255-0857.93014 Abstract Human immunodeficiency virus type-2 (HIV-2) belongs to the family retroviridae which is phylogenetically clusters with SIV SM from sooty mangabeys. This virus is morphologically similar to human immunodeficiency virus type-1 (HIV-1) but has got only a 40% homology at the nucleotide level. There is a distinct geographical distribution of HIV-2 unlike HIV-1. There are currently eight subtypes/groups identified with subtype/group A responsible for the majority of infections. HIV-2 shows a considerable difference in the course of the disease. Clinical, haematological and immunological evaluation of individuals infected with HIV-2 has shown the virus to be less pathogenic than HIV-1 although the exact mechanism underlying this difference is not well defined. Similar to HIV-1, the HIV-2 isolates also showed distinct replicative and cytopathic characteristics. The transmission rate for HIV-2 compared to HIV-1 is very low both by heterosexual route and mother to child transmission. The clinical signs and symptoms of immunodeficiency associated with HIV-2 are similar to the ones seen among the HIV-1-infected individuals and they can also progress to AIDS. It is naturally resistant to NNRTI and hence the diagnosis become important as it affects the treatment strategy. Similar to HIV-1, HIV-2 strains of infected individuals also show mutations that can cause drug resistance. The current evidence suggests that there is no protective effective for HIV-2 against HIV-1. Keywords: Human immunodeficiency virus type-2, HIV, mutations, Drug resistance Introduction Human immunodeficiency virus type-2 (HIV-2) belongs to the family Retroviridae.[1] It was in 1985 that researchers found evidence for this second species of human immunodeficiency virus (HIV) among commercial sex workers (CSW) in Senegal (West Africa). The two types of HIV (HIV 1 and HIV 2) belong to different lineages and represent recent cross-species transmissions from different sources. [2] In the phylogenetic analysis, the HIV-1 clusters with SIV CPZ from chimpanzees (Pan Troglodytes) and HIV-2 with SIV SM from sooty mangabeys (Cercocebus atys) and with SIV MAC from macaques. [2] Acquired immune deficiency syndrome (AIDS) could currently be considered as a zoonosis. [3] Sooty mangabeys seen in several West African countries are naturally infected with SIV SM ; there is a geographic concordance between the HIV-2 endemic area and the natural habitat of sooty mangabeys. There is a good opportunity for frequent contacts between humans and sooty mangabeys because these animals are frequently kept as pets or hunted for food. It is estimated that in time both HIV-1 and HIV-2 may have evolved from a common ancestor and HIV-2 around 1940. [2] A combination of phylogenetic, molecular clock and coalescent analyses provided an estimation of the most recent common ancestor for HIV-2 subtype A and subtype B to be year 1940 ± 16 and 1945 ± 14, respectively. [4] The demographic estimates suggest transition of HIV-2 from endemic to an epidemic problem during 1955-1970. [4] Geographical distribution The prevalence of HIV-2 remains highest among the West African countries like Guinea Bissau, Ivory Coast, Senegal, Burkina Faso, The Guinea, Ghana and Gambia. During the late 1980s, the infection rate was very high in Guinea Bissau, where 6-10% of the population in the capital city was infected with HIV-2. [5] In Europe, most of the cases were reported from Portugal, Spain and France with highest prevalence in Portugal. [6] Majority of the infections reported in Asia were from India. [7],[8] The first report of HIV-2 in India was from the port city of Mumbai in 1991 and soon after infected individuals were identified from south Indian port cities of Chennai and Visakhapatnam. [8] Seroepidemiological surveys carried out during 1985-1987 in the major urban areas of six West African countries of Senegal, Guinea, Guinea Bissau, Mauritania, Burkina Faso, Ivory Coast showed moderate to high rates of HIV-2 seropositivity in all countries except Mauritania. [9] The seroprevalence varied from of 0.2% to 9.2% among the control groups of healthy individuals, pregnant women and prisoners. The overall prevalence rates of HIV-1, HIV-2 and dual infection with HIV-1 and HIV-2 in a 7-year prospective study conducted in Guinea-Bissau among a cohort of police offices and pregnant women were 0.9%, 9.7% and 0.5%, respectively. [10] The prevalence rates in the pregnant women were 0.9%, 5.5% and 0.2%, respectively for HIV-1, HIV-2 and dual infections. The prevalence of HIV-1 increased significantly during the study period in contrast the HIV-2 prevalence went down significantly between both the populations. The total incidence of HIV-1 was 0.74 and of HIV-2 was 0.83 per 100 person-years. The incidence of HIV-1 increased slightly (not significant) from 0.62 to 0.78 per 100 person-years. However, the incidence of HIV-2 declined significantly from 0.90 to 0.35 per 100 person years during the study period. [10] A 5-year analysis of immunoblotting results from a south Indian hospital population during 1993-1997 showed the frequency of HIV-2 infection to be 3.8% of the total HIV infection. Among this, 2.1% was dual infection and 1.7% was monotypic infection. Subsequent data from the same centre based on a HIV-2-specific ELISA had shown that the frequency of HIV-2 (both monotypic and dual) infection during the period of 2000-2001 to be 2.47% of the total HIV infection. [11] Testing 200 archived samples from 1988 to 1990 in Maharashtra state, India, showed 14 serapositive for HIV-2 and 14 positive for both HIV-1 and HIV-2. [12] In a report on national surveillance on HIV from France between January 2003 and June 2006, 10,184 new diagnoses were reported; the proportions of HIV-2 and HIV-1 group O infections were 1.8 and 0.1%, respectively. The transmission in the infected individuals was through heterosexual contact at the corresponding endemic area. [13] Genetic diversity of HIV-2 The genetic variability in HIV is generated by the lack of proof reading ability of the reverse transcriptase enzyme, the rapid turnover of the virus in vivo, host selective immune pressures and recombination events that are taking place during replication. [14] The surface envelope glycoprotein of the prototype HIV-2 and HIV-1 showed a homology of 40% at the nucleotide level. The V3 loop of the HIV-2 is reported to be the immunodominant region containing the neutralizing, antibody-dependant cellular cytotoxicity (ADCC) epitopes and implicated in cell membrane fusion, syncytia formation and infectivity. [15] Sankale et al showed that the average sequence heterogeneity within a sample for HIV-2 was 1.4% (Range 0-4.1%). This difference was significantly lower than the 6.1 % observed in the V3 loop of HIV-1. The average inter-patient nucleotide variability rate in the healthy HIV-2 seropositve patient was 0.6% compared to the 2.0% observed in patients with clinical AIDS. This higher sequence variability suggesting sequence heterogeneity could be associated with disease progression. [16] The reason for the lesser variability may be that HIV-2 replicates more slowly than the HIV-1. As in the case of HIV-1, phylogenetic clusters have also been described for HIV-2. There are eight subtypes/ groups identified till-date designated as A to H. [17] Unlike HIV-1, they do not show any difference in geographical distribution as all are found in West Africa. The two most prevalent HIV-2 subtypes are the A and B. A majority of the HIV-2 characterised till-date appears to be subtype A reported from most of the West African countries. Subtype B viruses seems to be much more geographically limited. It is reported from Abidjan, Ivory Coast, France and Portugal. Subtypes C, D, E and F are designated based on the analysis of partial sequences of viral genomes. Subtype C and D were identified from Liberia and subtype E and F were reported from Sierra Leone. [17] The new subtype, G, is represented by the phylogenetic analysis of full-length genomic sequences of a strain collected from an asymptomatic blood donor from Ivory Coast. [18] There are several reports on the genetic analysis on HIV-2 isolates from India. Grez et al have analysed the DNA sequences encoding the surface envelope glycoprotein of HIV-1 and HIV-2 from seven dually infected Indian individuals. [19] HIV-1 specific PCR products were amplified from all the seven individuals while HIV-2 pro-viral DNA was amplified only from 5 individuals. The nucleotide sequences divergence among the 7 HIV-1 strains varied between 3.1 and 6.8% (mean 5.7). The divergence among the 5 HIV-2 isolates was between 5.6% and 10.5% (7.7%). This low level nucleotide divergence seen among the HIV-1 and HIV-2 isolates in this study indicated a recent introduction of these viruses into the Indian subcontinent. The higher degree of divergence observed among the HIV-2 strains compared to the HIV-1 strains may imply that the HIV-2 infection preceded the onset of HIV-1 infection in this group of infected individuals. This study also first time confirmed the existence of dual infection in India by molecular technique. [19] The blast analysis of the sequences for V 3 region from 11 south Indian strains from the monotypic HIV-2 and the one from the dually infected individuals showed a high degree of relatedness to subtype A. [20] All the 12 strains showed a nucleotide homology in the range of 85-95% with subtype A strains isolated from western India during 1991-1992. The mean pair-wise genetic distance among the south Indian strains was 7.8%, similar to the one reported (7.7%) for the five strains from western India in 1991. The HIV-2 strains circulating in India have not undergone any significant divergence in the V3 region during the 10 years period (1991-2001) indicated by the minimal percent divergence of sequences between the sequences from western India and south India. [20] The full-length envelope gene (2.5 kb) of one of the strains of HIV-2 infection detected in Calcutta (India) was sequenced. [21] Phylogenetic analysis revealed a close relatedness to the HIV-2 ROD strain, sequence isolated in offshore Senegal. This strain, however, showed a genetic diversity of 13.5% to other Indian HIV-2 isolates. [21] Genomic analysis of HIV-2 subtype A isolates from India showed close relatedness to West African HIV-2 isolate. [22],[23],[24] This confirms a geographical entry route of HIV-2 to India from the African continent. Transmission of HIV-2 Heterosexual transmission The difference in the global spread of HIV-1 and HIV-2 may be a reflection of the difference in the basic reproductive rate of the two viruses, due to the differences in transmissibility and duration of infectiousness. The countries where the HIV-2 prevalence was higher initially have HIV-1 becoming more prevalent now. [25],[26] An 8-year prospective seroincidence survey conducted among the CSWs, a population of women considered at high risk for HIV infection, registered in a clinic in Dakar, Senegal, during 1985-1993 showed an overall difference in the rates of new infection of HIV-1 and HIV-2. [25] The incidence of HIV-2 over the 8 years of the study was 1.11 per 100 person-years. There was no significant increase in the calendar year specific incidence of HIV-2 and the prevalence of HIV-2 was constant throughout the study. The overall HIV-1 incidence was the same as HIV-2 but there was a pronounced increase in the annual incidence of HIV-1 during the study period. In 1991, the incidence of HIV- 1 infections exceeded that of the HIV-2 in the cohort. The incidence of HIV-1 rose to 2.81 per 100 person years, while that of HIV-2 was 1.25 years per 100 person-years. The HIV-1 incidence during 1992 was 2.19 per 100 person years and that for HIV-2 was 0.73 per 100 person years. Based on the above findings, the authors suggested a doubling time of 5.7 years for HIV-1, while the doubling time projected for HIV-2 was 31 years. These projections clearly indicated the divergent differences in the transmission rate of HIV-1 and HIV-2 at the population level. [26] Vertical transmission Mother-to-child transmission of HIV-2 is reported although it is very minimal compared to HIV-1. The rates of HIV-2 infection reported form the paediatric population is very low. The rates of serological concordance between HIV-2-infected mothers and their living children were low. [27] A community study conducted in Bissau, West Africa, during 1987 to 1989 failed to detect a single case of vertical transmission of HIV-2. [28] A prospective study carried out among 18,099 women who delivered between 1990 and 1992 in Abidjan, Ivory Coast, showed the rate of transmission of HIV-2 to be 1.2% compared to the 24.7% observed among the HIV-1-infected individuals. [29] Although dually infected mothers can transmit both the viruses, transmission usually involved only HIV-1. HIV-1-infected women had an approximately 21-fold greater risk of transmitting the infection to their children compared to HIV-2-infected ones. [29] Pathogenesis of HIV-2 At a cellular level One of the characteristic features of HIV and SIV is the high affinity interaction between gp120 `and the surface glycoprotein CD4. However, the CD4 molecule alone is not sufficient for the virus entry into the cell. There are at least 14, transmembrane G-protein (7GM)-coupled chemokine receptors that act as a co-receptor for the HIV and SIV infection. [30] The major co-receptors are the CCR5 and CXCR4. Like HIV-1, the primary isolates of HIV-2 also have the ability to use a broad range of chemokine receptors. [31] Primary HIV-2 isolates frequently use CCR5 like HIV-1 but show promiscuity in co-receptor usage. The efficiency of CD4-independent infection of HIV-2 is markedly higher than HIV-1. Affinity capillary electrophoresis (ACE)-analysis results showed that HIV-2 gp36 and HIV-1 gp41 have the common putative cellular receptor proteins P45 and P62. The binding of gp36 to human lymphocytes and monocytes could be based on the interaction between gp36 with P45 and P62. [32] A study describes the lack of association between the V3 genotype and viral phenotype of 18 Indian HIV-2 isolates. The study indicated that CCR5 coreceptor usage and NSI phenotype is predominant among Indian HIV-2 isolates obtained from patients in the early stage of infection. [33] Immunopathogenesis of HIV-2 infection The pathogenesis of HIV infection is closely related to the ability of the human immune system of the infected individual in cutting down the replication and spread of HIV. The pathogenesis of HIV-2 is different from that of the HIV-1 although the mechanism is the same. HIV-2 affects the immune system in the same manner as HIV-1. [34] The HIV-2-infected individuals also follow the same clinical disease progression as HIV-1. [34] The course of the disease in an infected individual varies from individual to individual; however, a common pattern of development has been recognised. The initial intensity of the HIV-specific immune response and the degree of virus-mediated immune activation are independent in an infected individual. Primary infection with HIV results in the induction of detectable level of both humoral and cellular immune responses against the virus. Subsequently, the individuals move into a prolonged asymptomatic period followed by the appearance of constitutional signs and symptoms that leads to death. [34] Compared to HIV-1-infected individuals, the number of productively infected cells in lymphoid tissues is significantly lower in HIV-2 infection. Clinical, haematological and immunological evaluation of individuals infected with HIV-2 has shown the virus to be less pathogenic than HIV-1. [35] However, the exact mechanism underlying this difference in the pathogenesis of HIV-1 and HIV-2 is not well defined. It may be because of the viral features or the response by the immune system of the individuals harbouring the virus. [36] The HIV-2 viral accessory protein vpx nuclear localisation signal is required for efficient infection of non-dividing cells. [37] Sexual transmission of HIV-2 is less efficient compared to HIV-1 M group and O groups, possibly because it is less infectious to dendritic cells in vitro models. [38] Infection with HIV-2 leads to a significant lower plasma viral load. [39] It also appears that the difference in plasma viral levels of HIV-1 and HIV-2 persists even into the late stages of the disease. One of the reasons for the difference in the natural course, transmissibility and epidemiological features may be the low plasma viral level. [39] It is also revealed that the viral ′set point′ is significantly lower in HIV-2 infection than it is reported among HIV-1-infected individuals. Recent HIV-2 seroconverters had 28 times lower plasma HIV RNA levels than recent HIV-1 seroconverters. [40] The mortality rate observed in the cohorts of HIV-1 and HIV-2 is found to be very different. In HIV-1-infected individual, the main determinant of future clinical progression of the disease to AIDS appears to be the HIV-1 plasma viral load. [41] Similar to HIV-1, the baseline plasma viral load predicts the rate of disease progression among HIV-2-infected individuals. [40] Simon et al have demonstrated that the cellular viral loads and detectable infectious virus in plasma from HIV-2-infected individuals were significantly lower than the HIV-1-infected individuals with CD4 counts of 200-500 cells/μl and this difference may be partly responsible for the differences in the epidemiological pattern of HIV-1 and HIV-2.[42] In HIV-infected asymptomatic individuals, the frequency of HIV-1 DNA in CD4+ T cells has been shown to increase considerably overtime in patients who ultimately develop rapidly progressive disease than patients with stable disease. There is a significant correlation between HIV-2 DNA load and clinical status of the infected individuals. Similar to HIV-1, the rate of isolation of HIV-2 from PBMC and plasma specimens was inversely proportional to the number of CD4+ T cells. [42] In a community study in which both HIV-1- and HIV-2-infected individuals were followed up, there were interesting findings. [43] The mean CD4% at the first presentation was significantly higher in HIV-2-infected individuals than in HIV-1-infected individuals even though the HIV-2 appeared in that community earlier than HIV-1. [43] The average fall in the CD4% among patients infected with HIV-2-infected individuals was 50% lower than that among HIV-1-infected individuals. The same study also observed that unlike HIV-1-infected patients, only less than twice that number with HIV-2 infection had presented to the hospital although the prevalence was three times higher for HIV-2 in that community than HIV-1. Generally, HIV-2-infected individuals were older than the HIV-1-infected individuals. [43] The frequency of isolation of HIV-2 virus correlated with the severity of infection. Similar to HIV-1, the HIV-2 isolates also showed distinct replicative and cytopathic characteristics and could be divided into two major groups: rapid/high and slow/low. [44] Rapid/high isolates, i.e. isolates with the ability to replicate in tumour cell lines, were usually isolated from individuals with symptomatic HIV-2 infection and lower CD4+ lymphocyte counts. These isolates induced syncytia in PBMC cultures, while the slow/low isolates unable to replicate continuously in tumour cell lines induced small syncytia, no cell death, or no cytopathic effect. The HIV-2 isolates obtained from asymptomatic individuals usually showed a slow/low replication pattern [44] The V3 loop of HIV-2 rapid/high isolates and slow/low isolates showing distinct differences with HIV-2 rapid/high isolates was more heterogeneous and had higher net charge. Studies on lymphoid histocultures carried out in vitro showed that the HIV-2 cytopathicity seems to be controlled similar to that of HIV-1. The ones which had specificity for CXCR4 were linked to an aggressive CD4+ T cell depletion phenotype. [45] In vitro studies have shown that the HIV-2 isolates utilising CD4-independent infection are more sensitive to antibody-mediated neutralisation. [46] Probably, HIV may be using CD4 as a protection mechanism to shield the conserved epitopes from neutralising antibodies in addition to the viral attachment. This higher sensitivity to neutralisation of CD4-independent strains of HIV-2 may partly be the reason for slower progression of disease among infected individuals. [46] Neutralising antibodies develop in most of the HIV-1-infected individuals against the primary infecting virus. During the later stage of infection, the virus escapes neutralisation. [47] However, irrespective of the stage of the disease, sera from HIV-2-infected individuals showed the neutralising antibody activity. [47] HIV-2-infected individuals with higher neutralising antibody activity have shown a low PBMC viral load. [47] This higher level of autologous neutralising activity may be one of the many reasons for the slower disease progression in the HIV-2-infected individuals. [47] The HIV-2 envelope protein gp105 is found to be more effective in inducing β-chemokines than gp120 of HIV-1. Cavaleiro et al ., have compared the immunosuppressive properties of the envelope proteins of HIV-1, HIV-2 and SIV to see if it has any role in the pathogenicity. [48] Interestingly, HIV-2 envelope protein gp105 showed the marked inhibitory properties on TCR-mediated lympho-proliferative responses than the HIV-1 and SIV. This marked immunosuppressive property could be beneficial to the host by interfering with the increased state of cellular activation. This in turn limits the establishment of viral replication. [48] Another reason for the difference in the life cycles and pathogenesis of HIV-1 and HIV-2 may be the ability of the HIV-2 envelope glycoprotein gp105 to bind with CD8 molecules in addition to CD4 molecules. [49] The binding of the gp105 to the CD8 molecule may induce phosphorylation of protein tyrosine kinase p56 ick in CD8+ T cell. This lead to the production of β chemokines as CD8+ T cells are main source of this β chemokine production. [49] Data from a case controlled study carried out in Guinea Bissau showed that pathogenicity in HIV-2 is not related to subtype. [26] In HIV-2-infected individuals, the higher mortality and lower CD4+/CD+ T cell ratios were associated with HIV-2-positive concordant partner than those living with HIV-2-negative partner . This study suggested the existence of two populations of HIV-2-infected individuals one that progress faster and die due to AIDS-related diseases and a second group that becomes non-progressors although both the populations were infected with the same genotype. The less pathogenic nature of the HIV-2 is further demonstrated by the survival of children born to HIV-1 and HIV-2 seropositive mothers. Studies conducted in West African countries showed that more children born to HIV-1-infected mothers died in comparison with those born to HIV-2-infected mothers. [29] Even though the pathogenicity of HIV-2 is lower than HIV-1, it is well documented that HIV-2-infected individuals can also have immunological defects when compared to normal healthy individuals. [50] HIV-2 seropositive individuals had significantly low CD4%, low total number of CD4 cells, low CD4/CD8 ratio and higher CD8% than HIV seronegative individuals. [50] Four-year follow up of the above cohort failed to demonstrate any significant progressive decline of CD4+ T lymphocytes. Cytotoxic T cells (CTL) have been identified among HIV-2-infected individuals showing an inverse correlation with proviral load indicating a protective role for CTL. [51] Yet another reason for the relatively benign course of the HIV-2 disease may be the reduced ability of the HIV-2 env glycoprotein to impair the myeloid function. Compared to the HIV-1 in which impairment of DC function may result from bystander effects of HIV-1 envelope proteins. However, HIV-2 env had no effects upon DC differentiation and maturation despite its broad receptor usage and ability to modulate monocyte function. [52] Role of Cytokines and chemokines in HIV-2 infection One of the major factors, which play an important role in the immunopathogenesis of HIV infection, is the aberrant immune activation. The ability of HIV to replicate in the CD4+ T cells is strongly influenced by immuno-regulatory cytokines. [36] The influence of tumour necrosis factor (TNF)-ά in HIV infection has been well characterised[53] The TNF-α induces the NF-κB site and can selectively kill HIV-infected cell. TNF-α is considered the amplifier of HIV infection and thereby the progression of the disease, vice versa the HIV infection indirectly amplifies the pathogenic effects of TNF-α.[53] Plasma level of TNF-α was significantly higher among HIV-1- and HIV-2-infected individuals compared to normal healthy controls.[36] The TNF-α levels were higher in HIV-1- than in HIV-2-infected individuals irrespective of CDC stages and remained stable during the course of the disease among HIV-2-infected individuals. The lower TNF-α observed may be one among the many reasons for the longer asymptomatic period seen among HIV-2-infected individuals. [36] Sousa et al., have compared percentage of interleukin (IL-2), interferon (IFN)-γ and IL-4 producing cells at the single cell level by flow cytometry. During the early stage of the disease, both HIV-2- and HIV-1-infected individuals showed the same proportions of IL-2-positive cells within the CD4+ T cell subset as the normal healthy controls. The frequency of cells able to produce IL-2 decreased in HIV-1-infected individuals, but it was maintained in HIV-2-infected individuals during progression of the disease. During the advanced stage of the disease, both HIV-1- and HIV-2-infected individuals had an increased frequency of IFN-γ- and IL-2-producing cells compared to normal healthy individuals. Compared to the controls, the HIV-2-infected individuals showed IFN-γ-producing cells within the CD8 T-cell population. In contrast to HIV-1-infected individuals, the proportion of IL-2+ IFN-γ+ cells within the CD8 subset was maintained in HIV-2 infection. This may have influence the ability of HIV-2-infected individuals to maintain the CD8 subset-specific responses in view of the proliferative capacity of these cells. [54] The slower CD4+ T cell decline in HIV-2-infected individuals may be due to the preservation of the T-cell ability to produce IL-2. The CD8 expansion favoured a beneficial role in HIV immunopathogenesis, rather than deleterious as HIV-2 showed a major expansion of the population of terminally differentiated effector CD8+ T cells with an attenuated HIV disease with low viraemia. [54] The asymptomatic monotypic HIV-2 individuals had a significantly higher plasma concentration of IL-10 compared to the normal healthy controls. The IL-10 level among the symptomatic HIV-2-infected individuals was significantly higher than asymptomatic individuals and during progression individuals showed an increase in IL-10 level. There was a significant positive correlation between the TNF-α level and CD8+ T cell counts in the monotypic HIV-2-infected individuals.[55] Increased lymphocyte proliferative response, gamma interferon and IL-2-producing T-cell responses are observed in untreated HIV-2 subjects with undetectable plasma HIV-2 levels. Clinical features The clinical signs and symptoms of immunodeficiency associated with HIV-2, as its early descriptions are similar to the ones seen among the HIV-1-infected individuals. Like HIV-1, HIV-2 virus infection can also progress to AIDS. [56] There are several reports of AIDS cases in HIV-2-infected individuals reported as early as late 1980s. [56] Opportunistic infections reported in these individuals were chronic diarrhoea, weight loss, and toxoplasmosis of the brain, candidal oesophagitis, pulmonary tuberculosis, other mycobacterial infections and Kaposi′s carcinoma. [56] The mean and median survival time after the diagnosis of AIDS were longer for HIV-2-infected individuals than for HIV-1-infected individuals even after adjustments for the CD4 count and age although the mean total number of opportunistic infections seen among both the cases was same. However, there was no observed difference in the mortality rate among the HIV-1, HIV-2 and dually infected individuals with < 200 CD4 cells although a significant lower mortality was observed among HIV-2-infected individuals with CD4 count of > 500 cells/μl. Laboratory methods for detection of HIV-2 infection The same diagnostic tests developed for the clinical diagnosis of HIV-1 are used for the diagnosis of HIV-2. The procedures include ELISA tests, rapid tests, immunoblotting for serodiagnosis and direct methods like virus culture, and detection of nucleic acids. Antigen detection analysis is well established for HIV-1. Serodiagnosis Even today, the well-accepted strategy for the serodiagnosis of HIV infection is by screening the sera by an ELISA followed by confirmation with a Western blot/immunoblotting. In a geographic area where a dual epidemic of HIV-1 and HIV-2 is ongoing, the critical first step in understanding the transmission, pathogenicity and prevention of HIV is the type-specific serodiagnosis of both the viruses. A testing algorithm for the diagnosis of HIV-2 was established by the Centers for Disease Control (CDC) and prevention and FDA by the use of HIV-1 and HIV-2 combination ELISA followed by confirmation with HIV-2 Western blot beginning from June 1992. All the currently available commercial ELISA kits in India for the diagnosis of HIV are incorporated with antigens from both the viruses. Infection with all subtypes of HIV-2, despite the inter subtype sequence differences of up to 25% in the gag, pol, and env regions, can be detectable by commercially available serological assays. One of the methods to differentiate the two types of HIV is to use a combination of highly sensitive and specific commercially available mono-specific ELISA. Nkengasong et al have proposed a reliable algorithm for the type-specific diagnosis of HIV infection. [57] They suggested the screening of the sera by a mixed HIV-1/HIV-2 ELISA followed by testing with HIV-1 and HIV-2 mono-specific ELISA. This approach has been shown to be more accurate than the assay based on immunoblotting. There were the two main advantages of this strategy. One was the cost which resulted in a cost saving of 59% compared to immunoblot testing, and the second advantage is that as the determination of reactivity is based on a calculated cut-off value, the subjectivity associated with interpreting weakly reactive immunoblotting bands was eliminated. [57] HIV-2 SPEIA using the specific immunodominant epitope from the envelope gp36 showed a 100% sensitivity with the HIV-2 n PCR (gold standard) confirmed samples. The specificity of the peptide ELISA was 95% and the likelihood ratio was 19.5. The overall concordance of the peptide ELISA with PCR findings was 96.8%. Considering the accuracy indices, the synthetic peptide ELISA can be considered as highly sensitive and specific. [58] Because of the 40-60% homology at the nucleic acid and amino acid level between HIV-1 and HIV-2, cross reactivity can occur during Western blot analysis leading to indeterminate observation. [59] The dual reactivity in the Western blot may also be due to the recombination of the two viruses. [59] Another important testing strategy for the screening of HIV in developing countries is using rapid tests. A combination of rapid tests with rapid synthetic peptide-based assay can provide the same quality of results provided by the conventional testing strategy based on immunoblotting. There are several rapid tests available commercially that can differentiate HIV-1 and HIV-2 infections. Although rapid HIV assays showed very good sensitivity (almost 100%) for the detection of HIV-1, the sensitivity reported for HIV-2 varies from assay to assay. A study from south India was able to detect all the 18 pure HIV-2 samples tested by two rapid kits. One of the kits used in that study was able to discriminate between HIV-1 and HIV-2 in 17 (94.4%) of the 18 pure HIV-2 infections and correctly identified the 7 true dual infections (PCR positives). [60] The rapid test for the diagnosis of HIV infection is found to be very cost-effective and is useful in centres where facilities are limited. In areas like the Indian subcontinent, where epidemic of both HIV-1 and HIV-2 infections are ongoing, it is important to use tests which can detect both these viruses. [11] Proviral DNA detection Serological methods like immunoblotting alone for the confirmation of HIV-2 are insufficient in a geographical area where both HIV-1 and HIV-2 epidemics are ongoing. Immunoblotting data requires reassessment with nPCR testing especially in putative dual infections. One of the direct methods for the diagnosis of HIV infection is detection of proviral DNA by PCR. DNA PCR is important in the detection of neonatal HIV infection and also to confirm the true serological activity of HIV-1 and HIV-2 in dual infection. Compared to the detection of HIV-1, the HIV-2 pro-viral DNA detection rate is lower and it varies from 52% to 95% depending on the nature of the PCR whether single or nested. [42],[61] A study from South India showed the nPCR to have a sensitivity of 93.3% among the individuals who were monotypic HIV-2 as ascertained by immunoblotting. The assay was 100% specific as none of the 30 HIV-1 samples (immunoblotting and PCR confirmed) were amplified by the nPCR for HIV-2. [58] The earlier reports on PCR confirmation of dual-positive samples showed a PCR-positive rate varying from 21% to 74 %. [61],[62] Peeters et al have emphasised the usefulness of molecular testing in addition to the routine serological markers to attain a better knowledge about the relative proportions of the different HIV types circulating within a community. [62] Prevalence estimation based entirely on serological methods may overestimate the prevalence of dual infection as indicated in their study which showed that more than half the individuals reactive for HIV-1 and HIV-2 antibodies were only infected with HIV-1 alone. These findings emphasise the difficulty of determining the HIV infection profile by the classical serological methods like Western blot in countries where both the HIV types are prevalent. Culture The HIV-2 isolates have distinct replicative and cytopathic characteristics similar to HIV-1. [44] Virus isolation for HIV-2 can be performed as it is done for HIV-1. The frequency of virus isolation of HIV-2 is comparatively lower than HIV-1. [44] However, there is striking similarity in the frequency of positive virus isolations between HIV-1 and HIV-2 and clinical status of the infected individuals. In both cases, the frequency of isolation increases with a decrease in CD4+ T cell, with progression of the disease. [44] In a first report on isolation of HIV-2 from India, Kulkarni et al, have reported isolation of two HIV-2 strains from peripheral blood mononuclear cells of two HIV-2 seropositive patients with pulmonary tuberculosis. Biological characterisation indicated both these isolates as syncytium inducing and produced cytopathic effect in T lymphoid cell lines. A neutralisation study on one of the isolates showed that it is related to the Senegal strain. [63] Syncytium formation was observed more frequently in patients with AIDS than asymptomatic individuals. Prognostic tests for HIV-2 CD4+ / CD8+ T-cell estimation and Plasma viral and proviral load The accepted standard technique for the enumeration of T-cell subset is flow cytometry. Currently, there are no commercially available kits that can detect the plasma RNA and/or proviral DNA of HIV-2. However, there are several in-house assays developed for the detection of HIV-2 viral load. [64] One of the important obstacles in the development of these assays is the genetic diversity observed in HIV-2 strains, similar to HIV-1. Damond et al have also developed a real-time PCR-based assay with primers targeting a conserved region in the central part of the gag gene for the detection of plasma HIV-2 viral RNA. [64] The detection limit of the assay was 250 copies equivalents/ml with good reproducibility. The assay showed a specificity of 100% and a sensitivity of 100% at 500 and 250 copies. The sensitivity was 66 % at 125 of copies/ml with good reproducibility. The real-time PCR was able to detect HIV-2 subtypes A, B and C. Treatment of HIV-2 infection The highly active antiretroviral therapy (HAART) for HIV involves at least three antiretroviral agents. The three important groups of agents available are the nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and the protease inhibitors (PI). Separate guidelines for the treatment of HIV-2 infections by HAART are not available probably because of the lack of information on viral dynamics of HIV-2 in an infected individual. Strong association of normal CD4+T cell counts and undetectable viral loads by in-house assays do not support the use of HAART in HIV-2-infected individuals. However, individuals with low CD4+ T cells, high viral loads and individuals with AIDS defining illnesses may benefit from the HAART therapy. [65] HIV-2 shows natural resistance to NNRTI as the amino acid sequences in the NNRTI binding site is different (only 60% identity) from that of HIV-1. Studies carried out on HIV-2 individuals, who were on anti-retroviral therapy, showed amino acid changes associated with drug resistance in the RT and protease gene at positions identical to those seen in HIV-1. A combination of ZDV, 3TC and LPV/r was shown to provide efficient and durable suppression of HIV-1 and HIV-2 for as long as 3 years in HIV-2-infected and dually infected patients. [66] In a prospective study of HIV-2 cohort in Senegal, patients were treated with nucleoside reverse-transcriptase inhibitor (NRTI) and PI (indinavir)-based regimens. Similar to HIV-1-infected individuals on ART, multiclass drug-resistance mutations (NRTI and PI) were detected in strains of 30% of patients. Resistance to at least one ARV class of drug was observed in 52% of individuals on treatment. The reverse-transcriptase mutations M184V and K65R, which confer high-level resistance to lamivudine and emtricitabine, were found in 43% and 9% of patients, respectively. The Q151M mutation, which confers multinucleoside resistance in HIV-2, emerged in strains from 9% of patients. Eight patients had PI mutations associated with indinavir resistance, which included K7R, I54M, V62A, I82F, L90M and L99F. Four of the patients had strains with multiple PI resistance-associated mutations. This study also showed that duration of therapy was positively associated with the development of drug resistance. Certain mutations like Q151M together with K65R or M184V were associated with high-level resistance to both lamivudine and Zidovudine in HIV-2. The combination of K65R, Q151M and M184V can lead to cross NRTI resistance. This may be because of the suboptimal regimens. [66] A Lopinavir/Ritonavir-containing regimen had shown good response as detected by an increase in CD4 cell count of at least 50 cells/΅l and undetectable HIV-2 RNA at 24 weeks. This shows the potential for Lopinavir/Ritonavir regimens as first-line therapy in HIV-2 infection. Moreover, there should be specific guidelines for treating HIV-dually infected patients so that it can avoid the use of NNRTI. Dual infection with HIV-1 and HIV-2 In geographical regions where a dual epidemic of HIV-1 and HIV-2 is ongoing, the serological reactivity to both the viruses in an infected individual may be a source of diagnostic difficulties. [11] The dual seroreactivity may be due to one of the following reasons, (a) a mixed infection; (b) broad immune response against infection with a single strain of HIV-1 or HIV-2; (c) infection with a unique third virus containing epitopes common to either viruses or (d) exposure to both viruses but established infection with only one. [67] The prevalence of dual seropositives infected with both HIV-1 and HIV-2 is highly dependent on the method used for the detection. Hence, more specific assays like monotypic synthetic peptide ELISA, specific PCR testing for either the viruses or culture are essential to find out the true positive status of HIV-2 and HIV-1 in dually infected people. PCR is an important method for the diagnosis and epidemiological studies of mixed HIV-1/HIV-2 infection. [67] The PCR positivity of dual infection on uncultured lymphocytes in the serologically positive dual infection varies from 21% to 95% in various reported studies. [61],[62] The PCR positivity varied depending upon the primers used and the amount of DNA input used for the amplification. [61] Doubling the amount of DNA can considerably increase the HIV-2 proviral detection by PCR. Does HIV-2 Protect against HIV-1 infection? In 1995, based on a cohort of Senegalese commercial female sex workers, Traverse et al demonstrated a significantly lower incidence of HIV-1 infection in HIV-2 infected than in HIV-uninfected female sex workers. [68] The HIV-1 incidence rate of 2.53 among the previously uninfected controls female sex workers was higher than the incidence rate of 1.06 among the HIV-2-infected sex workers, suggesting a protection of 68%. This observation was found to be significant although the HIV-2-infected individuals had significantly higher incidence of sexually transmitted diseases. Concurrent with this epidemiological study, a few in vitro studies also supported the above observation in which simultaneous infection of HIV-2 potentially inhibited the productive infection of peripheral blood lymphocytes by HIV-1. [67] Subsequent reports from six additional populations from western African countries have not substantiated the above findings. The findings from a cohort of Guinea-Bissau also reported a higher HIV-1 infection incidence rate among the HIV-2-infected individuals (2.63/100 py) than uninfected individuals (0.28/100 py). [69] Conclusion Globally, there are certain geographical areas where HIV-2 epidemic is ongoing along with HIV-1. Clinical, haematological and immunological evaluation of individuals infected with HIV-2 has shown the virus to be less pathogenic than HIV-1 although the exact mechanism underlying this difference is not well defined. Compared to HIV-1 the transmission rate is very low either through the heterosexual route and mother to child transmission. Similar to HIV-1-infected individuals, HIV-2-infected individuals can develop AIDS that can also show mutations which leads to drug resistance. References
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