Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection

A much better understanding of Integrase inhibitor modifications in HIV-1 populace genetics with combination antiretroviral remedy (cART) is essential for Integrase inhibitor creating eradication strategies. A examination for panmixia, however, confirmed major adjustments in inhabitants structure in 2/10 clients right after quick-expression cART (<1 year) and in 7/10 patients after long-term cART (1–15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident.

Anti-HIV compounds are highly effective for preventing the onset of AIDS but they do not cure infected individuals. Very low levels of virus remain detectable in the blood of most patients despite antiviral treatment and levels surge if treatment is stopped. It is crucial to understand why current treatments are not equipped to cure HIV infection so that new therapies addressing these shortcomings can be developed. By characterizing genetic sequences of HIV in patients before and during antiviral treatment, we found that the low levels of virus detected in the blood of treated patients did not result from newly infected cells but originated from cells, or the daughters of cells, that were already infected when treatment was initiated. This finding demonstrates that HIV present in blood after prolonged antiviral treatment is derived from cells infected prior to treatment which likely expanded over time through cell division. Such long lived, infected cells are likely the critical target for developing strategies to cure HIV infection.

The HIV-1 lifecycle includes rapid and error prone nucleic acid replication that results in large and genetically diverse virus populations in vivo. The consequences of broad HIV-1 genetic diversity include the presence of viral variants containing mutations that escape immune responses or confer resistance to individual antiretroviral agents. The use of antiretroviral agents in combination results in potent suppression of HIV-1 replication and reverses immune deficiency, at least in part. Despite the ability of cART to inhibit HIV-1 replication, treatment does not eradicate infection and plasma viremia persists at low levels in the majority of patients [1], [2]. If cART is discontinued, viremia rapidly rebounds to pre-therapy levels. Determining the sources and mechanisms for viral persistence during cART and rebound after interruption is essential for designing strategies to eradicate infection.

The dynamics of HIV-1 decay after initiating cART can be divided into four phases. The first phase, reflecting rapid clearance of ca 90% of productively infected cells with half-life of 1–2 days, is followed by a more gradual clearance of infected cells with a half-life of 2–3 weeks.