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Eliminating Persistent HIV Infection: Getting to the End of the Rainbow EDITORIAL
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Journal of Infectious Diseases, June 2007
David M. Margolis1,2,3 and Nancie M. Archin1
Departments of 1Medicine, 2Microbiology and Immunology, and 3Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill
(See the brief report by Chun et al)
The medical community's response to the first 25 years of the HIV pandemic has been remarkable. It was recently estimated that the return on this investment has already yielded 3 million years of life saved in the United States alone [1]. However, the steps forward in the next 25 years will be, in some respects, even more difficult.
Antiretroviral therapy (ART) can return dying patients to health, but we are now challenged to maintain this benefit for the life of every patient, to avoid the toxicities of long-term chemotherapy, and to expand access to life-saving therapy across the world. To state the obvious, the development of safe microbicides and an effective prophylactic vaccine are the key requirements needed for the long-term control of the HIV pandemic. However, as illustrated poignantly by the recent halt of 2 trials of a promising microbicide, many obstacles are before us on the long path to these goals.
In this issue of Journal, the work of Chun et al. [2] speaks to another challenge for the next generation of HIV research: the eradication of established HIV infection. HIV infection is currently incurable because of at least 2 therapeutic shortcomings: the inability of current therapy to interrupt all active viral replication in an individual, and the inability to target persistent proviral infection.
In 1998, a collaboration between a group at the National Institute of Allergy and Infectious Diseases and the University of Washington, Seattle, determined the speed with which quiescent, latent infection of resting CD4+ T cells is established in acute or early HIV infection [3]. Ten patients were identified with symptoms consistent with early HIV infection, and ART was initiated 10-120 days after the onset of symptoms. Measurements of persistent, latent infection were performed after as little as a week of therapy and after up to 17 months of therapy, demonstrating that latent infection of resting CD4+ T cells was immediately established at a frequency of about 1 infected cell per million resting CD4+ T cells. The size of the "latent pool" was not substantially different in patients treated within 10 days of the onset of symptoms, which might be as little as 3 weeks after initial exposure to HIV, than in patients treated weeks later.
In their report in this issue of the Journal, Chun et al. provide follow-up on 7 of the members of the original cohort studied serially after 31-54 months of ART. Strikingly, the frequency of latent infection plummets in the first 12-24 months of ART, to levels 10-100-fold lower than typically seen: between 2.5 and 15 infected cells per billion resting CD4+ T cells. The suggestion that latent infection decays rapidly in the first 12-24 months of therapy during early infection is consistent with findings reported by Strain et al. in a cohort of patients treated within 6 months of seroconversion [4].
However, although Chun et al.'s study finds that the half-life of latently infected resting CD4+ T cells in this cohort is the shortest ever reported (4.6 months), a close examination of the data suggests that, at least in 4 of the patients studied, a second, slower phase of decay appears to exists. If so, the frequency of infection may not diminish to much less than 1 cell per billion after years of therapy. In this case, given the 110 billion resting CD4+ T cells carried by the average human [5], the few infected cells remaining may be enough to reignite infection. And, of course, the possibility exists that HIV may rarely persist in cells other than resting CD4+ T cells or that circulating resting cells somehow underrepresent infection in resting cells in the tissue.
As suggested by Chun et al., some patients who have undergone early ART for extended periods of time may choose to discontinue therapy. However, a conceptual challenge to interruption of ART in this setting is the evidence of ongoing low-level HIV replication in many patients [6-9]. Although HIV RNA is often undetectable in the cerebrospinal fluid of highly suppressed patients, ongoing low-level replication in the central nervous system despite ART is of concern [10]. Studies thus far of HIV replication in gut-associated lymphoid tissue suggest that ART may not be maximally effective at this primary site of lymphoid tissue replication [11]. It seems likely that improvements in current ART or alternate approaches are needed to target cellular or anatomic areas of potential pharmacologic inadequacy. As Chun et al. have done in the past, extensive study of cells and tissues in patients before and after treatment interruption would be critical to help us understand why infection was not extinguished, in the event that eradication is not observed.
So, what is the way forward from here? The treatment of acute HIV infection may set the stage for subsequent attempts at eradication. Programs developed using recent public health techniques to detect seronegative acute HIV infection [12, 13] are now being employed to help us better understand the factors that lead to transmission and to provide critical scientific insight for vaccine development and are being more widely considered as a public health measure to reduce the spread of HIV infection. These efforts may also result in a larger pool of patients treated during acute infection who may potentially benefit from future attempts at eradication of infection.
Targeted approaches to disrupt latent infection or speed the clearance of persistently infected cells have been proposed [14-17]. We found that intensified ART and valproate could deplete latent infection [18], but a recent report has not measured decay in resting CD4+ T cell infection in patients receiving standard ART who were prescribed valproate for clinical reasons [19]. When comparing these studies, it is important to recognize that there are subtle differences in the challenging assays used to quantify resting CD4+ T cell infection, resulting in differences in the reported frequency of infection in patient cohorts that are clinically similar [18-20]. However, the observation of greatest relevance would be one that irrefutably demonstrates a progressive and substantial depletion of persistent proviral infection, regardless of methodology. To achieve this, more potent ART and/or more potent antilatency therapies may be needed.
If the activity of such approaches can be validated in careful studies of stable patients during chronic infection, the clinical benefit of therapies for proviral infection might then be tested in patients treated during acute infection, for which lifelong therapy may not be clinically mandated. Immunotherapies such as vaccines to augment anti-HIV immunity and to prevent viral rebound once ART is discontinued might also be tested in such patients. However, given the great clinical success of ART and recent improvements in the simplicity and long-term tolerability of antiretrovirals, the bar for improving over current therapy is high. Whereas considerable toxicity is acceptable during chemotherapy for malignancies, therapies that attempt to eradicate HIV infection must avoid undue risk and toxicity [21].
Clearly, much work and many challenges lie ahead as we write the history of the second 25 years of AIDS. If we are able to continue to bring novel scientific insights to bear in clinically effective ways and to create access to these advances for the people who need them, the next chapter of the story will be even more impressive than the first.
References
1. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006; 194:11-9. First citation in article | Full Text | PubMed
2. Chun TW, Justement JS, Moir S, et al. Decay of the HIV reservoir in patients receiving of antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis 2007; 195:XXX-XX (in this issue). First citation in article
3. Chun TW, 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; 95:8869-73. First citation in article | PubMed | CrossRef
4. 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; 191:1410-8. First citation in article | Full Text | PubMed
5. Haase AT. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol 1999; 17:625-56. First citation in article | PubMed | CrossRef
6. Dornadula G, Zhang H, VanUitert B, et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA 1999; 282:1627-32. First citation in article | PubMed | CrossRef
7. 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; 340:1605-13. First citation in article | PubMed | CrossRef
8. Gunthard HF, Frost SD, Leigh-Brown AJ, et al. Evolution of envelope sequences of HIV-1 in cellular reservoirs in the setting of potent antiviral therapy. J Virol 1999; 73:9404-12. First citation in article | PubMed
9. Palmer S, Wiegand AP, Maldarelli F, et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 2003; 41:4531-6. First citation in article | PubMed | CrossRef
10. Marquie-Beck J, de Almeida S, Lazzaretto D, et al. Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients. J Neuro Virol 2006; 12:100. First citation in article | PubMed
11. Poles MA, Boscardin WJ, Elliott J, et al. Lack of decay of HIV-1 in gut-associated lymphoid tissue reservoirs in maximally suppressed individuals. J Acquir Immune Defic Syndr 2006; 43:65-8. First citation in article | PubMed | CrossRef
12. Pilcher CD, Fiscus SA, Nguyen TQ, et al. Detection of acute infections during HIV testing in North Carolina. N Engl J Med 2005; 352:1873-83. First citation in article | PubMed | CrossRef
13. Fiscus SA, Pilcher CD, Miller WC, et al. Rapid, real-time detection of acute HIV infection in patients in Africa. J Infect Dis 2007; 195:416-24. First citation in article | PubMed
14. Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. Coaxing human immunodeficiency virus type 1 from resting CD4+ T cells: can the reservoir of HIV be purged? AIDS 2004; 18:1101-8. First citation in article | PubMed | CrossRef
15. Van Lint C, Quivy V, Demonte D, et al. Molecular mechanisms involved in HIV-1 transcriptional latency and reactivation: implications for the development of therapeutic strategies. Bull Mem Acad R Med Belg 2004; 159:176-89. First citation in article | PubMed
16. Kulkosky J, Culnan DM, Roman J, et al. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood 2001; 98:3006-15. First citation in article | PubMed | CrossRef
17. Scripture-Adams DD, Brooks DG, Korin YD, Zack JA. Interleukin-7 induces expression of latent human immunodeficiency virus type 1 with minimal effects on T-cell phenotype. J Virol 2002; 76:13077-82. First citation in article | PubMed | CrossRef
18. Lehrman G, Hogue IB, Palmer S, et al. Depletion of latent HIV infection in vivo. Lancet 2005; 366:549-55. First citation in article | PubMed | CrossRef
19. Siliciano JD, Lai J, Callender M, et al. Stability of the latent reservoir for HIV-1 in patients receiving valproic acid. J Infect Dis 2007; 195:833-6. First citation in article | Full Text | PubMed
20. Chun TW, Nickle DC, Justement JS, et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest 2005; 115:3250-5. First citation in article | PubMed | CrossRef
21. van Praag RM, Prins JM, Roos MT, et al. OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. J Clin Immunol 2001; 21:218-26. First citation in article | PubMed | CrossRef
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