ports the hypothesis that the proinﬂammatory microenviro-
ment caused by local M. tuberculosis infection enhances HIV
transmission to M. tuberculosis–speciﬁc CD4
T cells in vivo.
The importance of Th1 cytokines in mediating protection from
TB is well documented [36, 37]. Rapid depletion of M. tuberculosis–
speciﬁc Th1 cells early in HIV infection could therefore be key to the
tremendous increase in the risk of developing TB. In contrast,
T cells persist until the late stages of HIV in
fection , and typically, CMV-associated pathology does not oc-
cur until the very late stages of AIDS, further supporting our hy-
pothesis that rapid depletion of M. tuberculosis–speciﬁc CD4
cells is important in the speciﬁc pathologic interactions of M. tuber-
culosis and HIV. However, despite the depletion of this important T
cell subset, only a minority of coinfected subjects develop TB soon
after HIV infection. Speciﬁc CD8
T cells, nonconventional T cell
subsets, or alternative sources of IFN-
, such as NK
cells, may compensate for some of the effector functions of the M.
tuberculosis–speciﬁc Th1 cells [8, 38]. In addition, Th17 cells that do
not produce IFN-
have been shown to participate in M.
tuberculosis–speciﬁc immunity . Such responses may still be
sufﬁcient in most cases to control M. tuberculosis after depletion of
M. tuberculosis–speciﬁc Th1 cells. Alternatively, host genetic poly-
morphisms affecting anti–M. tuberculosis immunity could account
for differences in susceptibility to disease. Finally, differences in
pathogen load or virulence may also contribute to different TB dis-
ease outcomes in subjects coinfected with HIV and M. tuberculosis.
Interestingly, early in HIV infection the pulmonary and nondis-
seminated form of TB predominates, whereas in patients with AIDS
who have very low CD4
cell counts, disseminated and extrapul
monary TB disease is frequently observed, indicating that even in
such subjects there is residual anti–M. tuberculosis immunity left
after acute HIV infection.
In conclusion, our results demonstrate that acute HIV in-
fection is associated with the rapid loss of M. tuberculosis–
speciﬁc Th1 cells in the peripheral blood. This contrasts with
the gradual decline of the total CD4
cell count during the
chronic phase of HIV infection and may be caused by direct
HIV infection of these cells. Taken together, these data sug-
gest a mechanism of rapid M. tuberculosis–speciﬁc Th1 cell
depletion that may contribute to the early onset of TB that is
often observed in latently infected individuals who become
We thank all of the HIV Superinfection Study (HISIS) participants and
the excellent staff at the Mbeya Medical Research Programme that con-
ducted the HISIS study, especially Weston Assisya, Frowin Nichombe,
Clemence Konkamkula, and Vera Kleinfeldt. Furthermore we would espe-
cially like to thank Natanya Sandler, Philip Scheinberg, and Jason Brenchley
(Vaccine Research Center, National Institutes of Health) for many exciting
discussions during the writing of the manuscript.
1. Li Q, Duan L, Estes JD, et al. Peak SIV replication in resting memory
T cells depletes gut lamina propria CD4
T cells. Nature 2005;
2. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M.
Massive infection and loss of memory CD4
T cells in multiple tissues
during acute SIV infection. Nature 2005; 434:1093–7.
3. Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis
of HIV infection: what the virus spares is as important as what it de-
stroys. Nat Med 2006; 12:289 –95.
4. Mehandru S, Poles MA, Tenner-Racz K, et al. Primary HIV-1 infection
is associated with preferential depletion of CD4
T lymphocytes from
effector sites in the gastrointestinal tract. J Exp Med 2004; 200:761–70.
5. Guadalupe M, Reay E, Sankaran S, et al. Severe CD4
T-cell depletion in
gut lymphoid tissue during primary human immunodeﬁciency virus
type 1 infection and substantial delay in restoration following highly
active antiretroviral therapy. J Virol 2003; 77:11708 –17.
6. Kaufmann SH, McMichael AJ. Annulling a dangerous liaison: vaccina-
tion strategies against AIDS and tuberculosis. Nat Med 2005; 11:S33–
7. World Health Organization. Frequently asked questions about TB and
HIV. 2008. Available at: http://www.who.int/tb/hiv/faq/en/. Accessed
16 October 2008.
8. Kaufmann SH. How can immunology contribute to the control of tu-
berculosis? Nat Rev Immunol 2001; 1:20 –30.
9. D’Souza S, Romano M, Korf J, Wang XM, Adnet PY, Huygen K. Partial
reconstitution of the CD4
-T-cell compartment in CD4 gene knockout
mice restores responses to tuberculosis DNA vaccines. Infect Immun
10. Alderson MR, Armitage RJ, Tough TW, Strockbine L, Fanslow WC,
Spriggs MK. CD40 expression by human monocytes: regulation by cy-
tokines and activation of monocytes by the ligand for CD40. J Exp Med
1993; 178:669 –74.
11. Hoshino Y, Nakata K, Hoshino S, et al. Maximal HIV-1 replication in
alveolar macrophages during tuberculosis requires both lymphocyte
contact and cytokines. J Exp Med 2002; 195:495–505.
12. Chapman AL, Munkanta M, Wilkinson KA, et al. Rapid detection of
active and latent tuberculosis infection in HIV-positive individuals
by enumeration of Mycobacterium tuberculosis-speciﬁc T cells. AIDS
13. Lalvani A, Nagvenkar P, Udwadia Z, et al. Enumeration of T cells
speciﬁc for RD1-encoded antigens suggests a high prevalence of la-
tent Mycobacterium tuberculosis infection in healthy urban Indians.
J Infect Dis 2001; 183:469 –77.
14. Sorensen AL, Nagai S, Houen G, Andersen P, Andersen AB. Puriﬁ-
cation and characterization of a low-molecular-mass T-cell antigen
secreted by Mycobacterium tuberculosis. Infect Immun 1995; 63:1710 –7.
15. Ulrichs T, Munk ME, Mollenkopf H, et al. Differential T cell responses
to Mycobacterium tuberculosis ESAT6 in tuberculosis patients and
healthy donors. Eur J Immunol 1998; 28:3949 –58.
16. Sester U, Junker H, Hodapp T, et al. Improved efﬁciency in detecting
cellular immunity towards M. tuberculosis in patients receiving immu-
nosuppressive drug therapy. Nephrol Dial Transplant 2006; 21:3258 –
17. Arroyo MA, Hoelscher M, Sanders-Buell E, et al. HIV type 1 subtypes
among blood donors in the Mbeya region of southwest Tanzania. AIDS
Res Hum Retroviruses 2004; 20:895–901.
18. Boehme C, Molokova E, Minja F, et al. Detection of mycobacterial li-
poarabinomannan with an antigen-capture ELISA in unprocessed urine
of Tanzanian patients with suspected tuberculosis. Trans R Soc Trop
Med Hyg 2005; 99:893–900.
19. Hoffmann O, Zaba B, Wolff B, et al. Methodological lessons from a
cohort study of high risk women in Tanzania. Sex Transm Infect
2004; 80(Suppl 2):ii69 –73.
HIV and Loss of M. tuberculosis–Speciﬁc Th1 Cells
JID 2008:198 (1 December)