Relationship between T Cell Activation and CD4+ T Cell Count in HIV-Seropositive Individuals with Undetectable Plasma HIV RNA Levels in the Absence of Therapy

Fewer than 1% of chronically HIV-infected individuals are capable of maintaining clinically undetectable plasma HIV RNA levels (<75 copies/mL) in the absence of antiretroviral medications [1–4]. We and others have been systematically recruiting these “elite controllers” to characterize fully the correlates of protective immunity. For example, controllers have much stronger polyfunctional HIV-specific CD8+ T cell responses than chronically HIV-infected patients maintaining antiretroviral treatment–mediated viral suppression [5], and they are enriched for protective class I HLA haplotypes associated with delayed disease progression [3, 6–11]. Furthermore, controllers maintain high frequencies of CD4+ T cells that secrete interleukin-2 and proliferate in response to HIV peptides [12, 13]. These observations have led to the consensus that controllers are capable of containing HIV replication at very low levels with strong and durable HIV-specific immune responses. Much less attention has been paid to the non–HIV-specific immune function of these individuals. Indeed, although lower plasma HIV RNA levels in the absence of antiretroviral therapy predict slower rates of clinical progression [14], the extent of viral replication may explain less than half of the variability in the rates of subsequent CD4+ T cell decline and progression to AIDS [15, 16], and some patients maintaining undetectable or nearly undetectable plasma HIV RNA levels in the absence of antiretroviral therapy have experienced clinical progression [4, 17]. These observations suggest that factors other than the level of viral replication contribute to immunodeficiency in HIV infection. One such factor is the ability of HIV to cause generalized T cell activation. We and others have demonstrated that higher CD8+ T cell activation levels are associated with more-rapid clinical progression and CD4+ T cell decline in untreated patients [18–23] as well as fewer antiretroviral therapy–mediated CD4+ T cell gains [24–27], independent of plasma HIV RNA level. T cell activation may distinguish pathogenic from nonpathogenic simian immunodeficiency virus (SIV) infection [28], and generalized T cell activation in the absence of viral infection appears to be capable of inducing CD4+ T cell depletion and immunodeficiency in a murine model [29]. To our knowledge, no study to date has specifically addressed whether controllers have abnormal levels of generalized T cell activation, potentially contributing to immunodeficiency. To address these issues, we compared T cell activation levels between controllers and 3 comparator groups: HIV-uninfected patients at risk for HIV infection from a study of nonoccupational postexposure prophylaxis, HIV-infected patients maintaining undetectable plasma HIV RNA levels as a consequence of antiretroviral therapy, and untreated HIV-infected patients with detectable viremia. We also assessed the relationship between T cell activation and CD4+ T cell counts among controllers. Finally, we explored indirect mechanisms by which HIV might cause T cell activation despite clinically undetectable plasma HIV RNA levels. Specifically, because mucosal translocation of bacterial products may contribute to T cell activation in HIV infection [30], we assessed the relationship between T cell activation and plasma lipopolysaccharide (LPS) levels among controllers.