|
Memórias do Instituto Oswaldo Cruz
Fundação Oswaldo Cruz, Fiocruz
ISSN: 1678-8060 EISSN: 1678-8060
Vol. 91, Num. 3, 1996, pp. 385-387
|
Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 91(1), May/June
1996
Co-Infection with HIV and Mycobacterium tuberculosis:
Immunologic Interactions, Disease Progression, and Survival
John L Ho
Division of International Medicine and Infectious Diseases,
Departments of Medicine and Microbiology, Cornell University
Medical College, 1300 York Avenue, Room A-421, New York, N.Y.
10021, U.S.A.
Code Number: OC96076
Size of Files:
Text: 14.4K
No associated graphics files
Key words: Mycobacterium tuberculosis - HIV - co-
infection
This article presents the hypothesis that co-infections
accentuate the intrinsic immunopathology of HIV and thereby
shorten the HIV disease free-interval and survival. Our
published experience with Mycobacteria tuberculosis (Mtb)
co-infection with HIV is reviewed. In this longitudinal study
of the efficacy of isoniazid prophylaxis we present evidence that
subclinical co-infections with Mtb shortened the interval
for onset of HIV disease and survival and that treatment with
isoniazid reversed this. Our preliminary data on lung
immunopathology in active tuberculosis is presented in another
paper in this issue by M Gloria Almeida and J Roberto Lapa e
Silva who show that inflammatory host factors are expressed in
the lung. Their expression in this millieu may mediate enhanced
HIV replication. Lastly, we will review the data on the
interactions between immune cells that trigger HIV replication
in a model of how sexually transmitted diseases may enhance HIV
transmission from men to women.
Over the last ten years, the paradox of how HIV infection
results in the destruction of the immune system, as measured by
the number of CD4+ T cells has recently been unraveled. Many
hypotheses have been advanced, including the most extreme, that
HIV does not cause AIDS. Our current understanding on the
relationship between viral production and turn-over of CD4+
lymphocytes indicates that billions of virions and infected cells
are destroyed every day (Wei et al. 1995, Ho et al. 1995a, Wain-
Hobson 1995).
This vividly illustrates the very hostile environment created
by the immune system. However, HIV counters by massive force of
numbers. So long as a few progenies survive to continue
replication HIV ultimately gains the upper hand when the immune
system can not keep up with the shear numerical assault of HIV.
Clinically this deadly combat is reflected by the clinical
latency period, the calm before the storm of HIV associated
illnesses and AIDS.
The accumulated data are provided by (i) longitudinal studies
showing that overall viral load increases over months and years,
(ii) progressive loss of CD4 lymphocytes being associated with
increasing viral burden, (iii) much more virions and HIV-infected
cells being evident than previously thought, and (iv) circulating
virus detected in peripheral blood are viruses that have escaped
from lymphoid organs, the site of HIV replication and destruction
of the virus (Rasz et al. 1986, Simmonds et al. 1990, Panteleo
et al. 1993, Embreton et al. 1993, Piatiak et al. 1993, Patterson
et al. 1993, , Wain-Hobson et al. 1993, Connors et al. 1993, Cao
et al. 1995). The most direct data were recently provided by two
research groups (Wei et al. 1995, Ho et al. 1995a) These
investigators demonstrated that the clearance of peripheral blood
virions (between 10^8 to 10^9 viruses) is paralleled by turn-over
of CD4 T cells (0.1 to 7 x 10^9). Furthermore, a daily relative
net loss of 0.02 to 0.2 x 10^9 CD4 T cells accounts for a slow
progressive depletion and the clinical latency of HIV
infection.
In this setting of the immunopathology of HIV, we hypothesize
that co-infection by other pathogens (eg, Mycobacterium
tuberculosis and Chlamydia trachomatis) enhance HIV
replication, tipping the balance in favor HIV and, thereby
shortening survival and potentially enhance HIV transmission.
Co-infections may enhance HIV replication by direct or by
indirect mechanisms that trigger viral replication.
Alternatively, co-infection may result in immune activation,
suppression or immune cell depletion that further affect HIV
replication or contribute to immunodeficiency. In this
symposium, we will outline the indirect mechanisms by which co-
infection enhance HIV replication. These factors are cytokines
triggered during the immune response to the co-infection,
reactive oxygen radicals, and cell-cell contact via the
engagement of specific surface receptors. These factors trigger
HIV replication or cell to cell transmission of HIV (Ho et al.
1995b, Lipton & Gendelman 1995, Bukrinsky et al. 1995).
Evidence that co-infection with M. tuberculosis shortens
the interval for HIV disease progression and survival is provided
by our published data in the Lancet of a cohort of
Haitians who were randomly assigned to receive either isoniazid
with vitamin B6 or vitamin B6 alone (Pape et al. 1993). Patients
were not given anti-retroviral agents because this is not the
standard of care available in Haiti. We showed that isoniazid
was effective in preventing active tuberculosis. We further
examined the potential effect of M. tuberculosis co-
infection on the natural history of HIV. For this analysis, we
excluded those who later developed tuberculosis. We found that
isoniazid prophylaxis prolonged the HIV disease-free interval and
survival. The prolongation of HIV disease free-interval and
survival by isoniazid appeared comparable to that of anti-
retroviral therapy. We speculated that immunologic mechanisms
triggered by co-infection with M. tuberculosis may
adversely affect HIV disease progression and shorten survival.
Containment of the bacilli one key feature of control of the
infection. The containment of tubercle bacilli within a
granuloma requires the generation of cytokines, including tumor
necrosis factor-alpha (TNF-alpha) (reviewed in Pape et al. 1993).
However, TNF-alpha is a potent enhancer of HIV replication, which
may in this case increase viral burden leading to HIV-related
diseases, AIDS and death. Isoniazid, by its ability to kill
M. tuberculosis, obviates the host immune response to
contain M. tuberculosis and thereby, lessens viral burden
and prolongs HIV symptom-free interval and survival.
Furthermore, the immune response during active tuberculosis has
been shown to prime peripheral blood cells and enhance their
susceptibility for HIV infection (Tossi et al. 1993).
Evidence that co-infection with sexually transmitted diseases
can enhance HIV replication and potentiate transmission is
provided by the recent Journal of Experimental Medicine
article reporting an in vitro model of HIV transmission
facilitated by C. trachomatis (Ho et al. 1995b). In this
work, we found that neutrophils from HIV-seronegative donors
induce HIV-replication from HIV-infected patients mononuclear
cells and cell lines. Furthermore, enhanced HIV replication was
mediated by cell-cell contact and the generation of reactive
oxygen radicals, because either partitioning of cells or removal
of reactive oxygen radicals by superoxide dismutase and catalase
abrogated the enhancement of HIV replication as well as the
production of pro-inflammatory cytokines and HIV. In addition,
engagement of surface ligand-receptors between cells has been
shown to enhance HIV replication (Pinchuk et al. 1995). This
in vitro model provides a biologic explanation for the
increased risk for acquiring HIV infection when co-infected with
an sexually transmitted disease. This may be related to the
local recruitment of neutrophils by any sexually transmitted
disease and the induction of infectious virus from mononuclear
cells present in semen.
In summary, we presented longitudinal data on co-infection with
M. tuberculosis contributing to enhanced HIV disease
progression and shorten survival. We also delineated potential
host factors that trigger production of infectious HIV and
thereby, increasing sexual transmission of HIV. We speculate
that co-infections mediate shorten HIV symptom-free time and
survival by triggering increased HIV replication and viral burden
that results in enhanced depletion of CD4 T cell and
immunodeficiency. Co-infection with opportunistic infections is
also the result of the immunopathology of HIV. Therefore, our
research efforts should be directed at (i) evaluating effective
prophylaxis or treatment for co-infections, (ii) delineating host
factors that enhance HIV replication, and (iii) seeking novel
strategies that interrupt the effects of these factors.
Undertaking these research approaches will likely result in
reducing HIV replication and viral burden and thereby increasing
duration of symptom-free interval and survival in HIV-infected
persons. Lastly, these approaches may also reduce HIV
transmission and thereby limiting the scope of the HIV pandemic
(Grosskurth et al. 1995).
ACKNOWLEDGEMENTS
To Dr WD Johnson for generous support, and all the co-workers
who are co-authors or participants of the cited studies.
REFERENCES
Bukrinsky MI, Nottet HSLM, Schmidtmayerova H, Gendelman HE 1995.
Regulation of nitrix oxide synthase activity in HIV-1 infected
monocytes: implications for HIV-associated neurologic disease.
J Exp Med 181: 735-745.
Cao Y, Ho DD, Todd J, Kokka R, Urdea M, Lifson JD, Piatak M, Chen
S, Hahn BH, Saag MS, Shaw GM 1995. Clinical evaluation of a
branched DNA signal amplification for quantifying HIV type 1 in
human plasma. AIDS Res Human Retroviruses 11: 353-
361.
Connors RI, Mohri H, Cao Y, Ho DD 1993. Increased viral burden
and cytopathicity correlate temparally with CD4+ T-lymphocyte
decline and clinical progression in human immunodeficiency virus
type 1-infected individuals. J Virol 67: 1772-1777.
Embreton J, Zupanic M, Ribas JL, Burke A, Racz P, Tenner-Raz K,
Haase AT 1993. Massive covert infection of helper lymphocytes and
macrophages by HIV during the incubation period of AIDS.
Nature 362: 359-362.
Grosskurth H, Mosha F, Todd J, Mwijarrubi E, Klokke A, Senkke A,
Mayaud P, Changalucha J, Nicoll A, ka-Gina G, Newell J, Mugeye
K, Mabey D, Hayes R. 1995. Impact of improved treatment of
sexually transmitted diseases on HIV infection in rural Tanzania:
randomized controlled trial. Lancet 26: 346:530-
6.
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M
1995a. Rapid turnover of plasma virions and CD4 lymphocytes in
HIV-1 infection. Nature 373: 123-126.
Ho JL, He S-h, Hu A-r, Geng J-y, Basile FG, Almeida MGB, Saito
AY, J Laurence, Johnson WD Jr 1995b. Neutrophils from human
immunodeficiency virus (HIV)-seronegative donors induce HIV
replication from HIV-infected patients' mononuclear cells and
cell lines: an in vitro model of HIV transmission
facilitated by Chlamydia trachomatis. J Exp Med
181: 1493-1505.
Kassim S, Sassan-Morokro M, Ackah A, Abouya LY, Digbeu H, Yesso
G, Coulibaly I-M, Coulibaly D, Whitaker PJ, Doorly R, Vetter KM,
Brattegaard K, Gnare E, Greenberg AE, Wiktor SZ, De Cock KM.
1995. Two-year follow-up of persons with HIV-1- and HIV-2-
associated pulmonary tuberculosis treated with short-course
chemotherapy in West Africa. AIDS 9: 1185-91.
Lipton SA, Gendelman HE 1995. Dementia associated with the
acquired immunodeficiency syndrome. N Engl J Med
332: 934-940.
Panteleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox
CH, Orenstein JM, Kotler DP, Fauci AS 1993. HIV infection is
active and progressive in lymphoid tissue during the clinically
latent stage of disease. Nature 362: 355-358.
Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr 1993. Effect of
isoniazid prophylaxis on incidence of active tuberculosis and
progression of HIV infection. Lancet 342: 268-
272.
Patterson BK, Till M, Otto P, Goolsby C, Furtada MR, McBride LJ,
Wolinsky SM 1993. Detection of HIV-1 DBA and mRNA in individual
cells by PCR-driven insitu hybridization and flow cytometry.
Science 260: 976-979.
Piatiak M, Saag MS, Yang LC, Cllark SL, Kappes JC, Luk K-C, Han
BH, Sahe GM, Lifson JD 1993. High levels of HIV-1 in plasma
during all stages of infection determined by competitive PCR.
Science 259: 1749-1754.
Pinchuk LM, Polacino PS, Agy MB, Klaus SJ, Clark EA 1995. The
role of CD40 and CD80 accessory cell molecules in dendritic cell-
dependent HIV-1 infection. Immunity 1: 317-325.
Racz P, Tenner-Racz K, Kahl C, Feller AC, Kern P, Dietrick M
1986. Spectrum of morphologic changes of lymph nodes from
patients with AIDS or AIDS-related complexes. Progr
Allergy 37: 181
Simmonds P, Balfe P, Peutherer JF, Ludlam CA, Bishop JO, Brown
AJL 1990. Human immunodeficiency virus-infected individuals
contain provirus in small numbers of peripheral mononuclear cells
and at low copy numbers. J Virol 64: 864-872.
Tossi Z, Sierra-Madero JG, Blinkhorn RA, Mettler MA, Rich EA
1993. Enhanced susceptibility of blood monocytes from patients
with pulmonary tuberculosis to productive infection with HIV-1.
J Exp Med 177: 1511-1516.
Wain-Hobson S 1995. Virologic mayhem (editorial). Nature
373: 102.
Wain-Hobson S 1993. Viral burden in AIDS (Scientific
Correspondence) Nature 366: 22.
Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, JD
Lifson, Bonhoeffer S, Nowak MA, Hahn BH, Saag MS, Shaw GM 1995.
Viral dynamics in human immunodeficiency type 1 infection.
Nature 373 :117-122.
This work was supported in part by National Institutes of Health
Grants R37-22624, D43-TW00018 and AI33322.
Fax: (212) 746-8675
Received 7 December 1995
Accepted 10 January 1996
Copyright 1996 Fundacao Oswaldo Cruz
|