Activation of virus replication after vaccination of HIV-1-infected individuals.

Abstract

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...

Glucocorticoids Regulate TCR-Induced Elevation of CD4: Functional Implications

“…Based on these observations, our experiments suggest that T cell activation may render the cell susceptible for HIV entry due to an increased expression of cell surface CD4. Indeed, previous studies have shown that activation of T cells strongly contributes to HIV replication (73)(74)(75)(76)(77). Up to now, however, these findings have been explained by an interplay of viral and host regulatory proteins, such as Tat, Rev, Nef, NF-B, and NF-AT.…”

No reactivation of attenuated immunodeficiency viruses in rhesus macaques after vaccinia virus-induced immune activation.

“…Lymphocyte stimulation by VV superinfection did not increase the virus load in monkeys infected with attenuated immunodeficiency viruses. In contrast, as shown for HIV-1 in immune-activated humans (O'Brien et al, 1995 ;Staprans et al, 1995 ;Stanley et al, 1996 ;Ro$ sok et al, 1996), in two macaques pathogenic SIV could temporarily be reactivated in vivo. Similar findings have been made by immune activation of macaques infected with pathogenic SIV during the primary phase of infection (Villinger et al, 1996).…”

“…This was shown for HIVseropositive individuals immunized with different common vaccines (O'Brien et al, 1995 ;Staprans et al, 1995 ;Stanley et al, 1996 ;Ro$ sok et al, 1996) or super-infected with immunestimulating bacteria (Goletti et al, 1996). In these reports, enhancement of virus replication seems to contribute to AIDS pathogenesis.…”

Opportunistic infection as a cause of transient viremia in chronically infected HIV patients under treatment with HAART

“…The observation of Di Mascio et al (2003a) that blip frequency is inversely correlated with baseline CD4+ T cell count suggests that patient specific factors, such as susceptibility to infection, which increases at low CD4 counts, may play a role in blip generation. Prior work on untreated, chronically infected HIV patients documents increases in viral load associated with vaccination (O'Brien et al, 1995; Staprans et al, 1995;Brichacek et al, 1996;Stanley et al, 1996) and with opportunistic infection (e.g., Donovan et al, 1996). McLean and Nowak (1992) proposed some of the first models of enhanced HIV replication due to immune stimulation via opportunistic infection, and showed how the positive feedback between enhanced HIV replication and incomplete immune control of pathogens due to HIV-immunosuppression leads finally to immune failure and full-blown AIDS.…”