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Objective: To investigate whether time-measured phylogenetic analysis of longitudinal viral sequences can establish the direction and timing of HIV-1 transmission in an epidemiologically linked transmission cluster of three homosexual men.Design: An HIV-1-infected homosexual man (patient 1) and his long-term HIV-negative partner (patient 2) engaged in a triangular relationship with an additional partner (patient 3). On the basis of phylogenetic analysis of gag sequences, patient 3 was previously identified as the source for superinfection of patient 1 but the source of HIV-1 infection of patient 2, who seroconverted during the triangular relationship, remained unclear. Here, we set out to analyze newly obtained gag, pol and env sequences from all three patients to fully elucidate the transmission history in this epidemiologically linked cluster.Methods: Bayesian Markov Chain Monte Carlo (MCMC) phylogenetic analyses incorporating a relaxed clock model and a flexible Bayesian skyride tree prior were applied to the longitudinally obtained gag, pol and env sequences from all three patients.Results: Our time-measured evolutionary reconstructions convincingly supported transmission of HIV-1 from the new partner patient 3 to both patients 1 and 2. In addition, estimates of viral divergence times assisted in narrowing down the transmission intervals delineated by seroconversion estimates.Conclusion: Our analysis implies that Bayesian MCMC phylogenetic reconstruction incorporating temporal information can indeed reveal the direction of multiple HIV-1 transmission events in an epidemiologically linked cluster and provide more detail on the timing of transmission. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Persistent reservoirs remain the major obstacles to achieve an HIV-1 cure. Prolonged early antiretroviral therapy (ART) may reduce the extent of reservoirs and allow for virological control after ART discontinuation. We compared HIV-1 reservoirs in a cross-sectional study using polymerase chain reaction-based techniques in blood and tissue of early-treated seroconverters, late-treated patients, ART-naïve seroconverters, and long-term non-progressors (LTNPs) who have spontaneous virological control without treatment. A decade of early ART reduced the total and integrated HIV-1 DNA levels compared with later treatment initiation, but not reaching the low levels found in LTNPs. Total HIV-1 DNA in rectal biopsies did not differ between cohorts. Importantly, lower viral transcription (HIV-1 unspliced RNA) and enhanced immune preservation (CD4/CD8), reminiscent of LTNPs, were found in early compared to late-treated patients. This suggests that early treatment is associated with some immunovirological features of LTNPs that may improve the outcome of future interventions aimed at a functional cure. DOI: http://dx.doi.org/10.7554/eLife.09115.001, eLife digest Many people with HIV infections are able to live relatively normal lives thanks to major advances in drug therapies. A cure, however, remains elusive. One reason for this is that the virus can hide in certain types of human cells, where it is protected from the immune system and the effects of “antiretroviral” drugs. This creates reservoirs of virus particles in the body that can quickly multiply and spread if treatment stops. Some people who become infected with HIV are able to contain the virus without the help of drug treatments. These individuals – known as long-term non-progressors – do not become ill and only have low numbers of HIV particles in reservoirs. People who receive treatment early in the course of an HIV infection also have fewer viruses in reservoirs and are less likely to develop severe illness. Therefore, it might be possible to develop a “functional” cure that may not completely eliminate the virus from the body, but would prevent illness and allow the individuals to eventually stop taking antiretroviral drugs. Now, Malatinkova, De Spiegelaere et al. studied samples from 84 patients with HIV-1 to find how much effect an early start to treatment has on the amount of the virus in reservoirs. People who started treatment soon after infection had lower levels of HIV-1 in their blood than people who started treatment later (even after 10 years of treatment). However, patients that started treatment early had higher levels of HIV-1 in the blood than the patients who were long-term non-progressors. All the patients had similar levels of HIV-1 in tissue samples taken from the rectum, regardless of when they started treatment. The experiments suggest that HIV-1 reservoirs form very soon after infection. Malatinkova, De Spiegelaere et al. found that in addition to reducing reservoirs of HIV-1, an early start to drug treatment reduced the ability of the virus to make copies of its genetic code. People who started treatment earlier also had healthier immune cells. Together, the experiments support the benefits of starting drug treatments as soon as possible after a person is infected with HIV-1. It is important to further characterize thoroughly the viral reservoir in patients with limited HIV-1 reservoirs and to look for other immune factors involved in virus control, in the search for a functional cure of HIV. DOI: http://dx.doi.org/10.7554/eLife.09115.002

Purpose of review To review recent published literature around three areas: long-term nonprogression/viral control; predictors of viral load set point/disease progression; and the potential impact of antiretroviral therapy (ART) in early HIV infection. Recent findings The natural course of untreated HIV infection varies widely with some HIV-positive individuals able to maintain high CD4 cell counts and/or suppressed viral load in the absence of ART. Although similar, the underlying mechanistic processes leading to long-term nonprogression and viral control are likely to differ. Concerted ongoing research efforts will hopefully identify host factors that are causally related to these phenotypes, thus providing opportunities for the development of novel treatment or preventive strategies. Although there is increasing evidence that initiation of ART during primary infection may prevent the immunological deterioration which would otherwise be seen in untreated HIV infection, recent studies do not address the longer term clinical benefits of ART at this very early stage. Summary A better understanding of the relative influences of viral, host, and environmental factors on the natural course of HIV infection has the potential to identify novel targets for intervention to prevent and treat HIV-infected persons.