HIV persists in a reservoir of latently infected CD4+ T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (TCM) and transitional memory (TTM) CD4+ T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in TCM cells in subjects showing reconstitution of the CD4+ compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in TTM cells from aviremic individuals with low CD4+ counts and higher amounts of interleukin-7–mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.

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HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naive T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

/pdf/post-treatment-hiv-1-controllers-with-a-long-term-55l7uyocjk.pdf

Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Although combination therapy for HIV infection represents a triumph for modern medicine, chronic suppressive therapy is required to contain persistent infection in reservoirs such as latently infected CD4+ lymphocytes and cells of the macrophage-monocyte lineage. Despite its success, chronic suppressive therapy is limited by its cost, the requirement of lifelong adherence, and the unknown effects of long-term treatment. This review discusses our current understanding of suppressive antiretroviral therapy, the latent viral reservoir, and the needs for and challenges of attacking this reservoir to achieve a cure.

/pdf/the-challenge-of-finding-a-cure-for-hiv-infection-3135rb40n8.pdf

The challenge of finding a cure for HIV infection.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)67098-5.pdf

Depletion of latent HIV-1 infection in vivo: a proof-of-concept study

Despite complete or near-complete suppression of human immunodeficiency virus (HIV) replication with combination antiretroviral therapy, both HIV and chronic inflammation/immune dysfunction persist indefinitely. Untangling the association between the virus and the host immune environment during therapy might lead to novel interventions aimed at either curing the infection or preventing the development of inflammation-associated end-organ disease. Chronic inflammation and immune dysfunction might lead to HIV persistence by causing virus production, generating new target cells, enabling infecting of activated and resting target cells, altering the migration patterns of susceptible target cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearance mechanisms from function. Chronic HIV production or replication might contribute to persistent inflammation and immune dysfunction. The rapidly evolving data on these issues strongly suggest that a vicious cycle might exist in which HIV persistence causes inflammation that in turn contributes to HIV persistence.

/pdf/immune-activation-and-hiv-persistence-implications-for-hmruz1ipy3.pdf

Immune activation and HIV persistence: implications for curative approaches to HIV infection

Patients in whom virologic suppression is achieved with highly active antiretroviral therapy (HAART) retain long-lived cellular reservoirs of human immunodeficiency virus type 1 (HIV-1); this retention is an obstacle to sustained control of infection. To assess the impact that initiating treatment during primary HIV-1 infection has on this cell population, we analyzed the decay kinetics of HIV-1 DNA and of infectivity associated with cells activated ex vivo in 27 patients who initiated therapy before or <6 months after seroconversion and in whom viremia was suppressed to <50 copies/mL. The clearance rates of cellular reservoirs could not be distinguished by these techniques (median half-life, 20 weeks) during the first year of HAART. The clearance of HIV-1 DNA slowed significantly during the subsequent 3 years of treatment (median half-life, 70 weeks), consistent with heterogeneous cellular reservoirs being present. Total cell-associated infectivity (CAI) after 1 year of treatment was undetectable (<0.07 infectious units/million cells [IUPM]) in most patients initiating treatment during primary infection either before (9/9) or <6 months after (6/8) seroconversion. In contrast, all 17 control patients who initiated HAART during chronic infection retained detectable CAI after 3-6 years of treatment (median reservoir size, 1.1 IUPM; P<.0005). These results suggest that treatment <6 months after seroconversion may facilitate long-term control of cellular reservoirs that maintain HIV-1 infection during treatment.

https://www.zora.uzh.ch/id/eprint/154177/1/ZORA_NL_154177.pdf

Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1.

While no significant physiologic function of hemoglobin A2 (Hb A2), the minor basic component of human hemoglobin, has been recognized, only its oxygen equilibria have been studied in detail. Since hemoglobin A2 and its oxidative denaturation product, hemichrome A2, bind to the red cell membrane, particularly to band 3, to a greater extent than do Hb A or hemichrome A, some of the properties of Hb A2 that might influence hemoglobin-membrane association were examined. Hemoglobin A2 exhibited slightly increased susceptibility to autoxidation to methemoglobin. No differences were noted between methemoglobins A and A2, including the rates of enzymatic reduction and stability of the heme-globin linkage. Oxyhemoglobin A2 had a slightly lower solubility in phosphate buffer than did hemoglobin A. While the hemichromes (prepared with phenylhydrazine) of hemoglobins A2 and A had the same optical spectra, the A2 hemichrome exhibited greater stability. It is suggested that the differences in products of oxidative denaturation may provide the basis for functional differences between hemoglobins A2 and A.

Ruby Y. Lam

Papers

Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1.

Some properties of hemoglobin A2.