Abstract
BackgroundWe have previously reported that CD4 T cells from some exposed uninfected (EU) Vietnamese intravenous drug users are relatively resistant to HIV infection in vitro. Here, we further characterized the restriction of viral replication in CD4 T cells from five EUs and assessed its persistence in serial samples.ResultsCD4 T cells and/or PBMC sampled during a period of between 2 and 6 years were challenged with replication-competent HIV-1 and other retroviral particles pseudotyped with envelope proteins of various tropisms. CCR5 expression and function in resistant CD4 T cells was evaluated. The step at which HIV-1 replication is restricted was investigated by real-time PCR quantification of HIV-1 reverse transcripts.We identified three patterns of durable HIV-1 restriction in EU CD4 T cells. CD4 T cells from four of the five EU subjects were resistant to HIV-1 R5 infection. In two cases this resistance was associated with low CCR5 surface expression, which was itself associated with heterozygous CCR5 mutations. In the other two cases, CD4 T cells were resistant to HIV-1 R5 infection despite normal CCR5 expression and signaling function, and normal β-chemokine secretion upon CD4 T cell activation. Instead, restriction appeared to be due to enhanced CD4 T cell sensitivity to β-chemokines in these two subjects. In the fifth EU subject the restriction involved post-entry steps of viral replication and affected not only HIV-1 but also other lentiviruses. The restriction was not overcome by a high viral inoculum, suggesting that it was not mediated by a saturable inhibitory factor.ConclusionVarious constitutive mechanisms of CD4 T cell resistance to HIV-1 infection, affecting entry or post-entry steps of viral replication, are associated with resistance to HIV-1 in subjects who remain uninfected despite long-term high-risk behavior.
Highlights
We have previously reported that CD4 T cells from some exposed uninfected (EU) Vietnamese intravenous drug users are relatively resistant to human immunodeficiency virus (HIV) infection in vitro
We have previously shown that some Vietnamese intravenous drug users who remained uninfected by HIV despite more than 15 years of drug use have low CD4 T cell permissiveness to HIV infection in vitro [11]
In four out of five cases (W278, B195, B184, W336), CD4 T cells were less susceptible to infection by a CCR5-tropic (R5) HIV-1 pseudotype (HIV-BaL), while they were permissive to infection by a CXCR4-tropic (X4) HIV-1 pseudotype (HIV-HxB2) and to HIV-1 particles pseudotyped with the G protein from vesicular stomatitis virus (HIVVSVG), which has a ubiquitous receptor and uses an endocytic entry pathway [27]
Summary
We have previously reported that CD4 T cells from some exposed uninfected (EU) Vietnamese intravenous drug users are relatively resistant to HIV infection in vitro. Cellular susceptibility to human immunodeficiency virus (HIV) infection in vitro varies widely among individuals [1,2] Both host genetic and acquired mechanisms regulate HIV-1 replication. The recent discovery of several molecules endowed with antiretroviral activity in mice and primates underlines the contribution of innate intracellular resistance to infection by HIV and other retroviruses [4]. Some of these molecules, such as the cytidine deaminase APOBEC3G, have been implicated in the restriction of HIV-1 replication in resting human T cells [5,6]. Resistance to HIV-1 infection in vivo has not so far been linked to the expression or genetic polymorphism of these restriction factors [7,8], but the efficiency of viral replication is likely to be determined in large part by the balance between required factors and restrictive factors
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