Novel immunological strategies for HIV-1 eradication.

Despite the significant advances in antiretroviral therapy (ART), HIV-1 is able to persist in cellular reservoirs. Preclinical studies suggest that the latent reservoir is established within days of virus exposure, even before virus can be detected in peripheral blood. Latently infected cells remain undetectable by the immune system and can persist for years without losing their ability to produce infectious virus when ART is discontinued. Novel concepts for viral eradication strategies combine pharmacological induction of latently infected cells to produce virus together with immune-enhancing interventions to enable the host to clear these cells. In this review, we describe the early establishment of HIV-1 latency and discuss current strategies to disrupt latency and potentially enable clearance of these persistently infected cells.

Infrequent recovery of HIV from but robust exogenous infection of activated CD4(+) T cells in HIV elite controllers.

BACKGROUND. Human immunodeficiency virus (HIV) elite controllers are able to control infection with HIV-1 spontaneously to undetectable levels in the absence of antiretroviral therapy, but the mechanisms leading to this phenotype are poorly understood. Although low frequencies of HIV-infected peripheral CD4(+) T cells have been reported in this group, it remains unclear to what extent these are due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication. METHODS. We assessed proviral DNA levels, autologous viral growth from and infectability of in vitro activated, CD8(+) T cell-depleted CD4(+) T cells from HIV elite controllers (mean viral load, <50 copies/mL), viremic controllers (mean viral load, <2000 copies/mL), chronic progressors, and individuals receiving highly active antiretroviral therapy. RESULTS. Although we successfully detected autologous virus production in ex vivo activated CD4(+) T cells from all chronic progressors and from most of the viremic controllers, we were able to measure robust autologous viral replication in only 2 of 14 elite controllers subjected to the same protocol. In vitro activated autologous CD4(+) T cells from elite controllers, however, supported infection with both X4 and R5 tropic HIV strains at comparable levels to those in CD4(+) T cells from HIV-uninfected subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contribute to difficulty in isolation of virus. CONCLUSIONS. These data indicate that elite control is not due to inability of activated CD4(+) T cells to support HIV infection, but the relative contributions of host and viral factors that account for maintenance of low-level infection remain to be determined.

Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses.

Effective HIV-specific T-cell immunity requires the ability to inhibit virus replication in the infected host, but the functional characteristics of cells able to mediate this effect are not well defined. Since Gag-specific CD8 T cells have repeatedly been associated with lower viremia, we examined the influence of Gag specificity on the ability of unstimulated CD8 T cells from chronically infected persons to inhibit virus replication in autologous CD4 T cells. Persons with broad (>or=6; n = 13) or narrow (

Metabolic and anthropometric changes one year after switching from didanosine/stavudine to tenofovir in HIV-infected patients.

BACKGROUND: Nucleoside analogues such as Didanosine and Stavudine are known to cause metabolic and body habitus changes during antiretroviral therapy. The most frequently observed are lactic acidosis, hypercholesterinaemia, hypertriglyceridaemia and lipodystrophy. METHODS: Over one year we monitored a cohort of 43 patients who switched from either Stavudine, Didanosine or the combination of both to Tenofovir. A group of 11 patients was kept on their original regimen and acted as control group. Blood samples were taken every 3 months from baseline, anthropometric measurements were performed at baseline, after 6 and 12 months. RESULTS: During observation the levels of lactic acid and cholesterol decreased significantly in the switch group while virologic and immunologic efficacy remained stable. Serum creatinine levels rose significantly in patients switched to Tenofovir, but remained within physiological limits. The mean skin fold thickness increased significantly by 1.8 mm in the switch group after 6 months (p < or =0.001 - p = 0.032). CONCLUSION: These results implicate an improvement of lipid profiles, serum lactate and lipodystrophy in HIV-positive patients after switch to Tenofovir. As a moderate increase in serum creatinine levels was observed, the renal function of patients on a Tenofovir-based regimen should be monitored closely.

Clinical news from the XVI International AIDS Conference: The attempt of a summing up.

Topics highlighted at the XVI International AIDS Conference in Toronto included HIV/AIDS vaccine research, entry inhibitors, integrase inhibitors, new NNRTIs and PIs, single-agent therapies, pre-exposure prophylaxis and microbicides. Beside the large scientific part, policy and funding were of great concern. Within this article we are trying to focus on topics with direct clinical relevance. This includes new epidemiological and resistance data, results from current studies investigating established and novel antiretroviral drugs and drug classes as well as new findings in therapy management and strategies.

Treatment interruption in HIV therapy: a SMART strategy?

Continuous HAART is standard of care for HIV-infected patients but lifelong adherence and tolerance are important concerns. Use of ART is associated with potential risks, e. g., adverse events, metabolic and cardiovascular complications, and HIV resistance. Stopping HIV therapy may reduce costs and side effects, but carries the risk of increased immune suppression and of emergence of resistance. Treatment interruption is a strategy of much interest, but its safety and efficacy have not been established. The clinical and biological characteristics that influence the outcome of structured treatment interruptions have not been fully clarified. In the following we will present the results of recent studies aimed to compare the long-term consequences of two antiretroviral-management strategies: continuous therapy versus scheduled treatment interruption.

What's New in HIV/AIDS? Chemokine receptor antagonists: a new era of HIV therapy?

Chemokine receptors are essential for human immunodeficiency virus (HIV) cell entry. CXCR4 and CCR5 are the two most relevant receptors and by inhibition of each of them a delayed onset of disease could be achieved. As both receptors are used at different stages of disease due to the domination of different HIV strains, a dual blockage of CXCR4 and CCR5 could be highly valuable for inhibiting viral transmission and replication.

What's new in HIV/AIDS? Neutralizing HIV antibodies: do they really protect?

Neutralizing antibodies work as a second line of defence. They are detected more or less in nearly every HIV-1-infected individual. 2G12, 2F5 and 4E10 represent antibodies with broadly neutralizing activity made from B cells of HIV- 1-infected humans. Unfortunately these antibodies are extremely rare and all attempts to elicit them via vaccine immunogens have failed. The discovery of autoreactive features of these antibodies could now explain why. Additionally, new results show the delayed viral rebound under antibody treatment in some HIV-1-infected individuals.

HIV genetic diversity: any implications for drug resistance?

At least nine different genetic HIV-1 subtypes and several circulating recombinant forms exist, which in addition to HIV-1 subgroups and HIV-2 account for the global AIDS pandemic. Even though HIV-1 subtype C and A predominate globally, antiretroviral drugs have been designed based on sequences of clade B reverse transcriptase (RT) and protease enzymes due to the domination of HIV-1 subtype B in highly industrialized countries. Since there is no clarity about possible effects of the genetic diversity of HIV-1 on therapy outcome and drug resistance, multiple studies have been performed with divergent results. Up to now this question remains to be answered.

Susceptibility to HIV/AIDS: an individual characteristic we can measure?

Susceptibility to HIV-1 infections is, beside other factors, determined by individual host genetic variants like HLA class I alleles, CCR5 and CCR2 variants and levels of CCR5 binding chemokines. A new approach to determine the individual risk of acquiring an HIV infection or to estimate the disease progression could now be possible. In a recent study, a significant interindividual and interpopulation difference in the copy number of a segmental duplication encompassing the gene encoding CCL3L1, a potent human immunodeficiency virus-1 (HIV- 1)-suppressive chemokine was found. Possession of a CCL3L1 copy number lower than the population average was associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This could lead to a screening test that identifies people who have a higher or lower susceptibility to HIV/ AIDS, potentially enabling clinicians to adapt treatment regimens. Also, this is particularly important for assessment of the efficacy of a protective vaccine.