The prevalence of HIV is increasing dramatically among adolescents and young adults in the United States. The NIH funded Adolescent Trials Network (ATN) will soon be implementing several different randomized controlled trials of novel treatment strategies aimed at improving adherence, minimizing toxicity, and enhancing HIV- specific immune responses in this group. These include structured treatment interruptions (STIs) and induction- maintenance (IM) treatment regimens. A concern arising from these non-standard approaches is the selection of drug resistant HIV that may become stably fixed in the latent reservoir of resting CD4+ T-cells. The fixation of drug -resistant HIV in the latent reservoir could have a dramatic impact on future therapeutic options because it guarantees life-long persistence of archival drug- resistant HIV. We hypothesize that treatment which allows for fluctuations in antiretroviral drug levels or that are less able to inhibit ongoing rounds of viral replication will give rise to drug- resistant variants that can be detected before overt treatment failure ensues, and that these variants may become permanently archived in the latent reservoir in resting CD4+ T cells. The first specific aim is to evaluate the evolution of genotypic drug resistance during novel treatment strategies that employ STIs or indcution-maintenance regimens. Sensitive molecular methods for genotyping plasma virus at <50 copies/ml will be used for longitudinal assessment of drug- resistant HIV emerging after STIs or during switches to less potent regimens. The second specific aim is to measure new infection of susceptible cells by drug- resistant variants arising during novel treatment strategies in infected adolescents. Infection of monocytes, a recently arising population with limited circulation time, will be assessed longitudinally to determine whether newly emergent drug- resistant viruses are fully infectious. The third specific aim is to determine the capacity of recently generated drug- resistant HIV variants arising during novel treatment strategies to become fixed in the latent reservoir for HIV in resting CD4+ T-cells. The entry of newly generated drug-resistant HIV in the latent reservoir will be assessed in longitudinal studies of adolescents receiving novel HAART. The clinical specimens and analytic resources available within the ATN provide a unique opportunity to study HIV pathogenesis in infected adolescents.
