[show abstract][hide abstract] ABSTRACT: We have previously associated high natural killer (NK)-cell activity and protection against HIV-1 infection in Vietnamese exposed uninfected intravascular drug users (EUs). Considering that activating and inhibitory signals sensed by NK-cell receptors regulate NK-cell activation, we performed phenotypic and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) transcript analyses of the NK-cell receptor (NKR) repertoire in 25 EUs, 19 HIV(+) intravenous drug users, and 26 uninfected blood donors. Although NK-cell activation was not linked to a unique NKR repertoire in EUs, various patterns consistent with NK-cell activation were detected in EUs: high KIR3DS1/KIR3DL1 ratio associated with down-regulated KIR3DL1 transcript levels, KIR2DL3(+) low-affinity receptor expansion associated to group HLA-C1 ligand in 2DS2(-)/2DL2(-) EUs, enhanced NKG2C/NKG2A ratio, and increased CD69 expression. Remarkably, EUs exhibited high constitutive degranulation activity in the absence of exogenous stimulation, as shown by the CD107a assay. Furthermore, CD161 expression was increased within the CD107a(+) NK-cell compartment. Our results suggest that in response to viral exposition, particular genetic or regulated features of the NKR repertoire of EUs contribute to their high constitutive NK-cell potential. This might allow NK cells to generate a more rapid and effective immune response to HIV-1, thereby contributing to prevention toward infection.
[show abstract][hide abstract] ABSTRACT: To assess immunological parameters, including markers of immune activation, in highly HIV-1-exposed uninfected (EU) Vietnamese intravascular drug users (IDUs) in comparison with HIV-1-infected IDUs and HIVunexposed controls, we determined peripheral lymphocyte phenotypes in fresh whole blood samples from 32 EU IDUs, 28 HIV+ IDUs, and 26 blood donors. We found higher levels of activation markers (CD38, HLADR) on CD4+ and CD8+ T cells, lower percentages of naive CD4+ and CD8+ T cells, higher percentages of CD8+ T cells and of CD8+ T cells expressing CD25, and lower levels of CXCR4+CD4+ T cells in EU IDUs than in unexposed controls. Despite several differences in CD4+ and CD8+ T cell subset phenotypes, both EU and HIV+ IDUs exhibited a pattern of peripheral immune activation. Lymphocyte activation in EU IDUs may reflect immune stimulation driven by viral infections other than HIV-1 and/or allogeneic stimulation associated with needle sharing. Our results suggest that immune activation does not necessarily favor HIV-1 transmission, but, on the contrary, may alter the susceptibility of EUs to HIV-1 infection and contribute to their resistance.
AIDS Research and Human Retroviruses 04/2006; 22(3):255-61. · 2.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: To identify mechanisms of resistance to HIV-1 infection in exposed uninfected individuals.
We examined in-vitro cell susceptibility to HIV-1 infection in highly exposed Vietnamese intravascular drug users (IDU) who, despite a history of more than 10 years of drug use and a high prevalence of other blood-borne viral infections, remain apparently HIV uninfected.
Forty-five exposed uninfected IDU and 50 blood donors were included in the study. Peripheral blood mononuclear cells (PBMC) or CD4 cell susceptibilities to HIV infection were evaluated using three HIV-1 isolates with different tropisms. Polymerase chain reaction analysis of HIV-1-DNA replication intermediates was used to characterize the restriction of HIV-1 replication in CD4 cells. Homologous CD8 cells were mixed with infected CD4 cells to evaluate their role in virus suppression.
We observed a relative resistance to PBMC infection with HIV-1 in 21 out of 45 exposed uninfected IDU, but only in five out of 50 unexposed controls (P < 0.001). PBMC resistance was related either to an inhibition of HIV-1 replication in CD4 cells or to CD8 cell-mediated viral suppression. HIV-1 replication in CD4 cells was restricted at the early stages of the viral cycle.
Reduced PBMC susceptibility to HIV-1 infection was associated with resistance to infection in exposed uninfected IDU. Distinct mechanisms are involved in in-vitro resistance and may contribute to the apparent protection from HIV-1 transmission in this systemically exposed population.
AIDS 07/2003; 17(10):1425-34. · 6.41 Impact Factor