Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis

Abstract

The absence of immune defects that occurs in the syndrome of long-term nonprogressive (LTNP) HIV infection offers insights into the pathophysiology of HIV-induced immune disease. The (H[F/S]RIG)2 domain of viral protein R (Vpr) induces apoptosis and may contribute to HIV-induced T cell depletion. We demonstrate a higher frequency of R77Q Vpr mutations in patients with LTNP than in patients with progressive disease. In addition, T cell infections using vesicular stomatitis virus G (VSV-G) pseudotyped HIV-1 Vpr R77Q result in less (P = 0.01) T cell death than infections using wild-type Vpr, despite similar levels of viral replication. Wild-type Vpr-associated events, including procaspase-8 and -3 cleavage, loss of mitochondrial transmembrane potential (Δψm), and DNA fragmentation factor activation are attenuated by R77Q Vpr. These data highlight the pathophysiologic role of Vpr in HIV-induced immune disease and suggest a novel mechanism of LTNP

Mechanisms of apoptosis induction by the HIV-1 envelope

“…Thus, the apoptogenic effect of Vpr is only revealed when using pseudotyped viruses, that is genetically modified HIV-1 strains in which the endogenous Env gene has been replaced by nonapoptogenic Env proteins from other viruses. 8,11 This underscores the idea that Env is, at least in vitro, the principal apoptosis-inducing protein encoded by the HIV-1 genome. [12][13][14][15] The Env glycoprotein (gp) precursor protein (gp160) undergoes proteolytic maturation to generate gp41 (membrane inserted) and gp120 (membrane inserted or shed from the cell surface).…”

“…5,6 Clinical case reports 7 and epidemiological data 8 that await confirmation suggest that loss-of-function mutations affecting the apoptogenic action of Vpr 9,10 are more frequent in viral isolates from long-term nonprogressors (untreated patients with diagnosed HIV-1 infection for 410 years, with CD4 T cell count of 4500 Cells/ mm 3 ) than in patients developing AIDS. Conversely, mutations that truncate the putative glutathion peroxidase gene tend to be more frequent in AIDS patients than in long-term nonprogressors (Cohen et al, 2004), again underscoring the notion that a higher apoptogenic (or a lower antiapoptotic) potential of HIV-1 accelerates AIDS pathogenesis.…”

“…In viral infection assays involving wild-type HIV-1, the apoptogenic effect of a clinically important HIV-1-encoded protein such as Vpr 8 is not observable due to the intrinsically high apoptosis-inducing effect of the HIV-1-encoded envelope glycoprotein complex (Env). Thus, the apoptogenic effect of Vpr is only revealed when using pseudotyped viruses, that is genetically modified HIV-1 strains in which the endogenous Env gene has been replaced by nonapoptogenic Env proteins from other viruses.…”

Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism

“…First, mutations to key amino acids of Vpr have been associated with long-term nonprogressive HIV infections. 4 Second, patient-erived viral isolates with normal capability to replicate but without cytotoxicity have been described. These viruses contain Q3R mutations and premature stop codons in vpr.…”

Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions

“…Vpr was shown to locate predominantly in the nucleus or at the nuclear membrane [25,53,54], but not in the mitochondria. In addition, it has been reported that Vpr activates caspase-8 [55,56] which should not be activated in the intrinsic MOMP pathway.…”