Slow Human Immunodeficiency Virus Type 1 Evolution in Viral Reservoirs in Infants Treated with Effective Antiretroviral Therapy

Abstract

A longitudinal study of viral reservoirs in children initiating highly active antiretroviral therapy (HAART) in early infancy was undertaken to test the hypothesis that early effective treatment affects the persistence of replication-competent viral latency and the evolution of HIV-1 in resting CD4(+) T cells. An end point dilution culture assay was used to measure the frequencies of latently-infected resting CD4(+) T cells harboring replication-competent virus in early and late treated children. Gag, pol, and env also were sequenced and compared to pretreatment sequences. HIV-1-specific humoral and cellular immune responses were also assessed. Blood samples were obtained from 12 HIV-1-infected children who started HAART at a median of 1.9 months of age and who maintained suppression of HIV-1 replication for up to 5.5 years. Replication-competent HIV-1 was recovered from 10/12 (84%) subjects. Evolution in gag, pol, and env was restricted for years in early-treated children. HAART initiated from early infancy does not prevent the establishment of a reservoir of latent provirus, but does significantly limit the evolution of HIV-1 in viral reservoirs. The effect of early therapy on HIV-1 evolution may have implications for long-term pharmacologic control of HIV-1.

Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA

“…Q 2 VOA maximizes the yield of limiting dilution cultures to obtain viruses originating from a single cell. Consistent with the absence of viral evolution in individuals on suppressive ART, Q 2 VOA revealed that the latent replication-competent viral population is similar between time points 4-6 mo apart (12,13,38). This interval is relatively short in the life of an infected individual, and it will be interesting to evaluate the reservoir by Q 2 VOA over longer time intervals.…”

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time

“…Investigations into whether HIV-1 replication continues during suppressive therapy have been carried out with peripheral blood and GALT samples but have led to potentially contradictory results. Some studies have found an absence of genetic evolution in viral reservoirs (23)(24)(25)(26)(27)(28)(29) and no reduction of plasma RNA during intensification of cART…”

Use of Animal Models for Anti-HIV Drug Development

“…Recent reports suggest that ongoing viral replication does not occur during suppressive therapy in humans, based on a lack of viral evolution (Bailey et al, 2006;Kieffer et al, 2004;Nottet et al, 2009;Persaud et al, 2007). This was also observed in RT-SHIV-infected monkeys with sustained plasma virus suppression (Kearney et al, 2011).…”