HIV Tropism and CD4+ T-Cell Depletion

LETTERS TO THE EDITOR 1Department of Surgery, 2Department of forebrain. J. Neurosci. 19, 3287–3297 (1999). 12. Shih, C.-C. et al. A secreted and LIF-mediated stro- Anatomy and Cell Biology, 5. Vescovi, A.L. et al. Isolation and cloning of multi- mal cell-derived activity that promotes ex vivo ex- potential stem cells from the embryonic human pansion of human hematopoietic stem cells. Blood 3 The Ontario Cancer Institute and Department CNS and establishment of transplantable human 95, 1957–1966 (2000). of Medical Biophysics neural stem cell lines by epigenetic stimulation. 13. Clarke, D.L. et al. Generalized potential of adult Exp. Neurol. 156; 71–83 (1999). neural stem cells. Science 288, 1660–1663 (2000). University of Toronto, Toronto, Ontario, Canada 6 Galli, R. et al. Emx2 regulates the proliferation of 14. Davis, A.A. & Temple, S. 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Gritti, A. et al. Multipotential stem cells from the factors behave as mitogenic regulators for a sin- Forman, S.J. Long-term ex vivo maintenance and adult mouse brain proliferate and self-renew in re- gle multipotent stem cell-like population from expansion of transplantable human hematopoi- sponse to basic fibroblast growth factor. J. the subventricular region of the adult mouse etic stem cells. Blood 94, 1623–1636 (1999). Neurosci. 16, 1091–1100 (1996). HIV tropism and CD4+ T-cell depletion To the editor—We fully support the con- with a more rapid rate of CD4+ T-cell tive, detrimental effect. The direct dam- clusions reached by Grossman et al.1 con- loss7. In patients who have only R5 HIV- age that is inflicted on the immune sys- cerning the critical role of immune 1 variants, immune activation is already tem by HIV-1 replication and the activation in HIV-1 pathogenesis. We chronic and strong, but increases signifi- indirect consequences of generalized im- also concur with the concerns they have cantly after X4 variants emerge8. mune activation together result in both expressed about incomplete and poten- Perhaps as important is the observa- accelerated CD4+ T-cell destruction, and tially flawed interpretations of the label- tion that R5 and X4 strains infect differ- an impaired ability of the immune sys- ing experiments used to determine the ent CD4+ T-cell subpopulations. R5 tem to regenerate and to repair the dam- rates of T-cell turnover in HIV-1 infec- viruses preferentially replicate in acti- age that it has incurred. If the virology © http://medicine.nature.com Group 2002 Nature Publishing tion2. vated, memory/effector T cells while X4 and immunology research communities There is no doubt that HIV-1 can de- viruses are also capable of infecting in- work together to understand this inter- stroy CD4+ T-cells both in vitro and in trathymic T progenitor cells and naive T play more completely, more effective vivo, but this cannot be the sole explana- cells in the peripheral lymphoid sys- long-term treatments for HIV-1 infection tion for HIV-1 disease progression. As tem9,10. Indeed, circulating naive CD4+ T might be designed. shown by studies of the natural hosts for cells are infected at high frequency in pa- simian immunodeficiency virus infec- tients with X4 virus and such infection is MARK B. FEINBERG1, JOSEPH M. tion, such as sooty mangabey monkeys associated with a drop in their num- MCCUNE2, FRANK MIEDEMA3, and African green monkeys, chronic bers10,11. Consequently, the emergence of JOHN P. MOORE4 & high levels of virus replication can be tol- X4 viruses in an infected person will HANNEKE SCHUITEMAKER3 erated without development of immun- both exacerbate ongoing chronic im- 1Emory University School of Medicine and the odeficiency disease3,4. As such, high-level mune activation and facilitate the de- Emory Vaccine Center, Atlanta, Georgia, USA replication of CD4+ T cell–tropic struction of the very cells that are 2Gladstone Institute of Virology and lentiviruses per se need not be lethal to involved in maintenance of the naive Immunology, University of California at San the host. Rather, it is the interplay be- and memory CD4+ T-cell pools. As a re- Francisco, San Francisco, California, USA tween the virus and the immune system sult, the regenerative capacity of the im- 3Sanquin Research at CLB and Landsteiner that converts what might otherwise be a mune system will collapse12. Laboratory, Academic Medical Center, benign infection to a lethal one1,3,5. In conclusion, we suggest that a com- University of Amsterdam, Amsterdam, the An important additional point of dis- plete and balanced understanding of Netherlands cussion is the phenotype of the HIV-1 HIV-1 pathogenesis is required for the 4Department of Microbiology and Immunology, strains that are present in infected hu- design of novel immune-based therapies Weill Medical College of Cornell University, mans6. Viruses that use the CCR5 core- to supplement the present therapies that New York, New York, USA ceptor for entry (R5 strains) predominate directly target the viral life cycle. The an- Email: [email protected] in the early stages of infection in virtu- tiviral immune responses of HIV-1-in- ally all HIV-1 infected individuals. fected adults and children can clearly be To the editor—I would like to comment However, phenotypic variants using the beneficial to the host, especially in the on the article by Grossman et al.1, since CXCR4 coreceptor (X4 strains) are even- short-term, but the sustained overstimu- my name has been on papers on both tually detectable in about 50% of in- lation of the immune system during sides of this debate. A key point raised by fected individuals and are associated chronic infection may have a cumula- these authors is the notion of biphasic NATURE MEDICINE • VOLUME 8 • NUMBER 6 • JUNE 2002 537.

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