The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

Treatment of human immunodeficiency virus type 1 (HIV-1, causative agent of AIDS) infection represents a major challenge in antiviral therapeutics. Many difficulties are associated with the treatment, including toxicity, resistance and high costs. Taking this into account, research for novel compounds able to overcome these limitations is needed. Sulfated polysaccharides appear to be interesting, given their abundance as components of seaweeds. Herein, a series of fractions obtained from the brown seaweed Adenocystis utricularis was analysed for in vitro anti-HIV-1 activity. These fractions, which have anti-herpes simplex virus activity, were determined previously to belong to the family of fucoidans, sulfated polysaccharides obtained from the cell walls of brown seaweeds. Assays in human PBMC primary cell culture demonstrated that two of the five fractions analysed had potent anti-HIV-1 activity both against WT and drug-resistant HIV-1 strains. For active fractions, it was also shown that the inhibitory effect was not due to an inactivating effect on the viral particle (i.e. no virucidal activity was detected) but rather to a blockade of early events of viral replication. Given these encouraging results, these seaweed-derived fractions appear as good candidates for further studies on their potential for in vivo therapy and/or prophylaxis of HIV-1 infection.

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PRMs occurred among 16.1% of relatively healthy HIV-1-infected mothers from Latin American and Caribbean countries receiving MTCT prophylaxis.

BackgroundCytotoxic T-Lymphocyte (CTL) response drives the evolution of HIV-1 at a host-level by selecting HLA-restricted escape mutations. Dissecting the dynamics of these escape mutations at a population-level would help to understand how HLA-mediated selection drives the evolution of HIV-1.Methodology/Principal FindingsWe undertook a study of the dynamics of HIV-1 CTL-escape mutations by analyzing through statistical approaches and phylogenetic methods the viral gene gag sequenced in plasma samples collected between the years 1987 and 2006 from 302 drug-naïve HIV-positive patients. By applying logistic regression models and after performing correction for multiple test, we identified 22 potential CTL-escape mutations (p-value<0.05; q-value<0.2); 10 of these associations were confirmed in samples biologically independent by a Bayesian Markov Chain Monte-Carlo method. Analyzing their prevalence back in time we found that escape mutations that are the consensus residue in samples collected after 2003 have actually significantly increased in time in one of either B or F subtype until becoming the most frequent residue, while dominating the other viral subtype. Their estimated prevalence in the viral subtype they did not dominate was lower than 30% for the majority of samples collected at the end of the 80's. In addition, when screening the entire viral region, we found that the 75% of positions significantly changing in time (p<0.05) were located within known CTL epitopes.ConclusionsAcross HIV Gag protein, the rise of polymorphisms from independent origin during the last twenty years of epidemic in our setting was related to an association with an HLA allele. The fact that these mutations accumulated in one of either B or F subtypes have also dominated the other subtype shows how this selection might be causing a convergence of viral subtypes to variants which are more likely to evade the immune response of the population where they circulate.