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AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.

We and others have reported that the vast majority of virus-producing CD4+ T cells during the acute infection of rhesus macaques with simian immunodeficiency virus (SIV) or CXCR4 (X4)- using simian/human immunodeficiency viruses (SHIVs) exhibited a nonactivated phenotype. These findings have been extended to show that resting CD4~ T lymphocytes collected from Sly- or X4-SHIV-infected animals during the first 10 days of infection continue to release virus ex vivo. Furthermore. we observed high frequencies of integrated viral DNA (up to 5.1 x 104 DNA copies per 105 cells) in circulating resting CD4+ T cells during the first 10 days of the infection. Integration of SIV DNA was detected only in memory CD4+ T cells and SHIVs preferentially integrated into resting naïve CD4+ T cells. Taken together, these results show that during the acute infection large numbers of resting CD4+ T cells carry integrated nonhuman primate lentiviral DNA and are the major source of progeny virions irrespective of coreceptor usage. Prompt and sustained interventions are therefore required to block the rapid systemic dissemination of virus and prevent an otherwise fatal clinical outcome. [ABSTRACT FROM AUTHOR]

CD8+ T cells are critical for effective host defenses against viral infections. Studies addressing HIV-induced immune responses in infected individuals have suggested that CD8+ T cells play an important role in controlling viral replication. However, despite an abundance of HIV-specific CD8+ T cells, HIV is not contained in many untreated patients. Active HIV replication is associated with numerous immunologic changes, the most notable and consistent of which is an increase in CD8+ T cells expressing CD38. Previous studies have demonstrated that the expression of CD38 on CD8+ T cells is associated with poor prognostic outcome in infected individuals with detectable plasma viremia; however, the relationship between the expression of CD38 and the frequency of HIV-specific CD8+ T cells is unclear. We demonstrate a correlation between levels of HIV-specific CD8+ T cells and levels of CD8+ I cells expressing CD38 in untreated patients. The distribution of HIV-specific CD8+ T cells was heavily skewed toward CD38+CD8+ T cells in patients with a high percentage of CD38+CD8+ T cells. Spontaneous/Fas-mediated apoptosis in CD38+CD8+ T cells was significantly higher in patients with high percentages of CD38+CD8+ T cells. Our data suggest that a substantial proportion of the HIV-specific CD8+ T cells present in CD38+CD8+ T cells in patients with active viral replication arise by HIV-driven aberrant immune activation and may not manifest effective cytolytic activity against infected targets due to a high degree of susceptibility to apoptosis, thus providing an explanation of why HIV is not successfully contained by CD8+ T cells in such individuals. [ABSTRACT FROM AUTHOR]

Discusses the developments in studies of latent reservoir of HIV in patients receiving highly active antiretrovial therapy and implications for the long-term treatment of infected individuals and eradication of the infection. Identification and characterization of the latent reservoir of HIV in resting CD4 T cells; Persistence of the latent HIV reservoir; Strategies for the elimination of latently infected, resting CD4 T cells.

Reports on a study which demonstrated that the highly active antiretroviral therapy's initiation in infected individuals with the human immunodeficiency virus-1 (HIV-1) infection, after the onset of symptoms of the infection, did not prevent generation of the latently infected CD4+ cells. Details on widespread dissemination of the HIV virus; In-depth look at CD4+ T cells; Methodology used to conduct the study; Results of the study.

The presence of HIV-1 in latently infected, resting CD4(+) T cells has been clearly demonstrated in infected individuals; however, the extent of viral expression and the underlying mechanisms of the persistence of HIV-1 in this viral reservoir have not been fully delineated. Here, we show that resting CD4(+) T cells from the majority of viremic patients are capable of producing cell-free HIV-1 spontaneously ex vivo. The levels of HIV-1 released by resting CD4(+) T cells were not significantly reduced in the presence of inhibitors of cellular proliferation and viral replication. However, resting CD4(+) T cells from the majority of aviremic patients failed to produce virions, despite levels of HIV-1 proviral DNA and cell-associated HIV-1 RNA comparable to viremic patients. The DNA microarray analysis demonstrated that a number of genes involving transcription regulation, RNA processing and modification, and protein trafficking and vesicle transport were significantly upregulated in resting CD4(+) T cells of viremic patients compared to those of aviremic patients. These results suggest that active viral replication has a significant impact on the physiologic state of resting CD4(+) T cells in infected viremic patients and, in turn, allows release of HIV-1 without exogenous activation stimuli. In addition, given that no quantifiable virions were produced by the latent viral reservoir in the majority of aviremic patients despite the presence of cell-associated HIV-1 RNA, evidence for transcription of HIV-1 RNA in resting CD4(+) T cells of aviremic patients should not necessarily be taken as direct evidence for ongoing viral replication during effective therapy.