Failure of potent protease inhibitor therapy to suppress HIV RNA levels below detectable levels is common in clinical practice, and can often be explained by their suboptimal use. CD4 T cell counts remain above baseline for at least one year in most patients experiencing virological failure. Successful salvage therapy, which was uncommon, was associated with a low plasma HIV RNA at the time of the switch and the use of a new class of antiretroviral agents (NNRTI) in the salvage regimen.

Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.

SummaryLittle is known about the factors that govern the level of HIV-1 replication in infected individuals. Recent studies (using potent antiviral drugs) of the kinetics of HIV-1 replication in vivo have demonstrated that steady-state levels of viremia are sustained by continuous rounds of de novo infection and the associated rapid turnover of CD4 + T lymphocytes . However, no information is available concerning the biologic variables that determine the size of the pool ofT cells that are susceptible to virus infection or the amount of virus produced from infected cells . Furthermore, it is not known whether all CD4+ T lymphocytes are equally susceptible to HIV-1 infection at a given time or whether the infection is focused on cells of a particular state of activation or antigenic specificity . Although HIV-1 replication in culture is known to be greatly facilitated by T cell activation, the ability of specific antigenic stimulation to augment HIV-1 replication in vivo has not been studied . We sought to determine whether vaccination ofHIV-1-infected adults leads to activation of virus replication and the targeting of vaccine antigen-responsive T cells for virus infection and destruction . Should T cell activation resulting from exposure to environmental antigens prove to be an important determinant of the steadystate levels of HIV-1 replication in vivo and lead to the preferential loss of specific populations of CD4 + T lymphocytes, it would have significant implications for our understanding of and therapeutic strategies for HIV-1 disease . To begin to address these issues, HIV-1-infected individuals and uninfected controls were studied by measurement of immune responses to influenza antigens and quantitation of virion-associated plasma HIV-1 RNA levels at baseline and at intervals after immunization with the trivalent influenza vaccine . Influenza vaccination resulted in readily demonstrable but transient increases in plasma HIV-1 RNA levels, indicative of activation ofviral replication, in HIV-1-infected individuals with preserved ability to immunologically respond to vaccine antigens . Activation of HIV-1 replication by vaccination was more often seen and ofgreater magnitude in individuals who displayed a T cell proliferative response to vaccine antigens at baseline and in those who mounted a significant serologic response after vaccination . The fold increase in viremia, as well as the rates ofincrease of HIV-1 in plasma after vaccination and rates of viral decline after peak viremia, were higher in individuals with higher CD4 + T cell counts . These data indicate that important aspects of the host-virus relationships underlying HIV-1 infection may be gleaned from the careful analysis of interventions that perturb, either positively or negatively, the steady-state equilibrium of virus replication in vivo . The potential adverse consequences of vaccine-induced activation of HIV-1 replication deserve consideration in formulating guidelines for immunization of HIV-1-infected individuals . Given the demonstra...

Some individuals in well-defined cohorts have now been infected with HIV-1 for well over a decade and yet remain clinically asymptomatic with normal CD4 counts. To determine immunologic and virologic parameters in these individuals, we examined 10 persons from the San Francisco City Clinic with firmly documented infection of 11-15 years duration who had maintained stable CD4 counts above 500 cells/microliters. Our results indicate that long-term nonprogressors are a heterogeneous group with respect to viral load and HIV-1-specific immune responses, and that progression can occur even after 15 years of stable infection. However, in a subset of persons with the lowest viral loads and persistent nonprogressive infection, we detected strong CTL responses, whereas neutralizing antibody studies revealed weak to undetectable titers against a panel of 10 primary isolates. This study demonstrates that a vigorous in vivo activated HIV-1-specific CTL response can be part of the host immune response in stable nonprogressive HIV-1 infection, and that circulating activated CTL can be detected in the setting of an extremely low viral load. These results also indicate that long-term nonprogressing HIV-1 infection does not require the presence of broadly cross-reactive neutralizing antibodies.

Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment.