点击显示 收起
Department of Medicine, Johns Hopkins University School of Medicine, and Howard Hughes Medical Institute, Baltimore, Maryland
Twenty-four years after the first cases of AIDS were reported, it remains unclear when therapy for HIV-1 infection should be initiated. The current Department of Health and Human Services guidelines suggest that treatment can be deferred until CD4+ T cell counts have fallen into the range of 200350 cells/L [1]. However, when the infection is diagnosed during the acute phase, treatment is considered to be "optional." The initial impetus for early treatment came from predictions that the infection might be eradicated by prolonged treatment with highly active antiretroviral therapy (HAART) [2]. Enthusiasm for the "hit early, hit hard" approach to treatment waned with the discovery that the virus could persist in a latent but replication-competent form in resting memory CD4+ T cells [3, 4]. These cells carry a stably integrated copy of the viral genome but do not produce virus unless they are activated in some way. Thus, latently infected cells allow viral persistence even in the presence of a vigorous immune response and potent antiretroviral drugs. This latent reservoir persists even in patients receiving HAART who have had prolonged suppression of viremia to below the limit of detection [59]. Because of the extremely long life span of memory T cells, this reservoir represents a formidable barrier to virus eradication. Because the reservoir is hard to target once established, there has been great interest in the idea that very early initiation of HAART during acute HIV-1 infection might prevent the establishment of this stable latent reservoir or at least reduce its size.
In the initial studies of the latent reservoir, it was noted that the latently infected cells persisted in patients who had initiated HAART as early as 10 weeks after presentation with acute retroviral syndrome [6, 10]. In a study of patients who initiated HAART within 4 months of presentation with acute retroviral syndrome, Chun et al. consistently detected latently infected cells harboring replication-competent virus at frequencies on the order of 1/106 resting CD4+ T cells [10], comparable to frequencies seen in patients who initiate HAART during chronic infection (1/1061/107). Normal or slightly reduced frequencies of latently infected cells were detected in several other studies of patients who initiated HAART during acute HIV-1 infection [1113]. When such patients interrupted therapy after 24 years, viral rebound was consistently observed [14, 15]. Taken together, these results suggest that a stable reservoir of HIV-1 is established early during infection.
In an interesting study in the current issue of the Journal of Infectious Diseases, Strain et al. [16] reexamine the important question of whether initiation of HAART during acute infection can reduce the size and/or increase the decay rate of the latent reservoir. They report that, after 1 year of HAART, cell-associated infectivity (a measure of the latent reservoir) had fallen to undetectable levels in most of the patients studied. Virus isolation was unsuccessful for 9 of 9 patients who initiated HAART very early (before seroconversion) and for 6 of 8 patients who initiated HAART <6 months after seroconversion. These results are potentially encouraging but somewhat surprising, in that the patients were treated with standard HAART regimens. In all other studies of the latent reservoir, infectious virus has been recovered from the majority of patients, regardless of when the patients initiated therapy or how long they had been receiving therapy [1013]. As Strain et al. point out, failure to recover infectious virus probably does not reflect the elimination of latently infected cells. More likely, the results reflect the fact that, in these patients, the frequency of latently infected cells has fallen below the limit of detection of the assay used. Even in chronically infected patients, latently infected cells are rare; typical frequencies are between 1/106 and 1/107 resting CD4+ T cells. Thus, detection is difficult. If the frequency is 1/107, then at least 10 million cells must be activated in culture to rescue infectious virus. In this situation, even a slight decrease in the frequency of latently infected cells in vivo will result in negative assays. It is most likely that the latent reservoir persists in these patients at a level that is below the sensitivity of the assay. Indeed, the authors report that some of these patients had episodes of detectable viremia during the study. Nevertheless, early treatment may have resulted in some reduction in the size of the latent reservoir, which is consistent with the findings of a previous study [11].
Although partial reductions in the size of the latent reservoir may not be useful, a therapeutic strategy that produces both a partial reduction in the size of the reservoir and an increase in its decay rate might resurrect hopes for eradication. Interestingly, Strain et al. also report a decay rate of the reservoir that is more rapid (half-life, 5 months) than the decay rate observed in patients who initiate HAART later during the course of infection (half-life, 44 months). However, as the authors observe in their article and in an elegant previous study [21], the decay rate appears to slow with time. This may reflect the fact that latently infected cells specific for frequently encountered antigens will be quickly removed from the reservoir by antigen-driven activation, leaving a more stable population of cells specific for rarely encountered antigens. It is also possible that differences in measured half-lives reflect the difficulties inherent in predicting the long-term behavior of a biological process on the basis of closely spaced observations close to the start of the process. It is sobering to consider that, in the only study of the latent reservoir that has examined patients receiving HAART for >5 years, an extremely long half-life (44 months) was observed [9]. Thus, further follow-up will be needed to determine whether early treatment establishes a more rapid trajectory of decay in these patients. For these reasons, the partial reduction in the size of the latent reservoir afforded by early treatment might be useful only in conjunction with novel therapies directed at eliminating the latent reservoir, as suggested by Strain et al.
Several arguments have been put forward to support the early initiation of HAART (see [22] for a review). There is no doubt that early treatment limits viral diversity, which may facilitate control. The immunologic benefits of initiating HAART early are complex and controversial [23]. A partial reduction in the size of the latent reservoir might add to the list of potential benefits, but only with the caveats discussed above. Balanced against these potential benefits are very real concerns related to problems that may develop during the extra years of treatment mandated by the early initiation of HAART. These problems include the risk of the development of resistance, drug toxicity, and cost. In the absence of any randomized controlled studies showing that treatment of primary HIV-1 disease provides long-term benefit, this remains a decision best left to clinical judgment.
References
1. Bartlett JG, Lane HC. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda, MD: US Department of Health and Human Services, 2004. First citation in article
2. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387:18891. First citation in article
3. Chun T-W, Finzi D, Margolick J, Chadwich K, Schwartz D, Siliciano RF. Fate of HIV-1-infected T cells in vivo: rates of transition to stable latency. Nat Med 1995; 1:128490. First citation in article
4. Chun T-W, Carruth L, Finzi D, et al. Quantitation of latent tissue reservoirs and total body load in HIV-1 infection. Nature 1997; 387:1838. First citation in article
5. Chun T-W, Stuyver L, Mizell SB, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 1997; 94:131937. First citation in article
6. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278:1295300. First citation in article
7. Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997; 278:12915. First citation in article
8. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5:5127. First citation in article
9. Siliciano JD, Kajdas J, Finzi D, et al. Long term follow-up studies confirm the extraordinary stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Med 2003; 9:7278. First citation in article
10. Chun T-W, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc Natl Acad Sci USA 1998; 95:886973. First citation in article
11. Lori F, Jessen H, Lieberman J, et al. Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir. J Infect Dis 1999; 180:182732. First citation in article
12. Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med 1999; 340:160513. First citation in article
13. Blankson JN, Finzi D, Pierson TC, et al. Biphasic decay of latently infected CD4+ T cells in acute HIV-1 infection. J Infect Dis 2000; 182:163642. First citation in article
14. Zhang L, Chung C, Hu B-S, et al. Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. J Clin Invest 2000; 106:83945. First citation in article
15. Markowitz M, Jin X, Hurley A, et al. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis 2002; 186:63443. First citation in article
16. Strain MC, Little SJ, Daar ES, et al. Effect of treatment during primary infection on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis 2005; 191:14108 (in this issue). First citation in article
17. Lassen KG, Bailey JR, Siliciano RF. Analysis of human immunodeficiency virus type 1 transcriptional elongation in resting CD4+ T cells in vivo. J Virol 2004; 78:910514. First citation in article
18. Persaud D, Pierson T, Ruff C, et al. A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children. J Clin Invest 2000; 105:9951003. First citation in article
19. Ruff CT, Ray SC, Kwon P, et al. Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure. J Virol 2002; 76:948192. First citation in article
20. Davey RTJ, Bhat N, Yoder C, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA 1999; 96:1510914. First citation in article
21. Strain MC, Gunthard HF, Havlir DV, et al. Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence. Proc Natl Acad Sci USA 2003; 100:481924. First citation in article
22. Kassutto S, Rosenberg ES. Primary HIV type 1 infection. Clin Infect Dis 2004; 38:144753. First citation in article
23. Kaufmann DE, Lichterfeld M, Altfeld M, et al. Limited durability of viral control following treated acute HIV infection. Plos Med 2004; 1:e36. First citation in article