Adaptive NK Cells Rapidly Expand during Acute HIV Infection and Persist Despite Early Initiation of Antiretroviral Therapy.

HIV is associated with NK cell dysfunction and expansion of adaptive-like NK cells that persist despite antiretroviral therapy (ART). We investigated the timing of NK cell perturbations during acute HIV infection and the impact of early ART initiation. PBMCs and plasma were obtained from people with HIV (PWH; all men who have sex with men; median age, 26.0 y) diagnosed during Fiebig stages I, II, III, or IV/V. Participants initiated ART a median of 3 d after diagnosis, and immunophenotyping was performed at diagnosis and longitudinally after ART. Anti-CMV Abs were assessed by ELISA. Samples from matched HIV-uninfected males were also analyzed. Proportions of adaptive NK cells (A-NKs; defined as Fcε-Receptor-1γ-) were expanded at HIV diagnosis at all Fiebig stages (pooled median 66% versus 25% for controls; p < 0.001) and were not altered by early ART initiation. Abs to CMV immediate early protein were elevated in PWH diagnosed in Fiebig stages III and IV/V (p < 0.03 for both). Proportions of A-NKs defined as either Fcε-Receptor-1γ- or NKG2C+/CD57+ were significantly associated with HIV DNA levels at diagnosis (p = 0.046 and 0.029, respectively) and trended toward an association after 48 wk of ART. Proportions of activated HLA-DR+/CD38+ NK cells remained elevated in PWH despite early ART initiation. NK cell activation and A-NK expansion occur very early after HIV transmission, before T cell activation, and are not altered by ART initiation during acute infection. A-NKs may contribute to HIV control and thus be useful for HIV cure.

A TNF Block Genotype may Influence CMV Retinitis in HIV Patients without Affecting Systemic Viral Replication.

BACKGROUND: A conserved TNF block haplotype marked by the minor alleles of rs1800629 (TNFA-308*A) and rs9281523 [BAT1(intron 10)*C] has been linked with several immunopathological conditions and with rapid progression of HIV disease. Reported associations with cytomegalovirus (CMV) retinitis in HIV patients before or during early antiretroviral therapy (ART) may therefore reflect greater replication of CMV in advanced HIV disease or an immunopathological response to CMV in the retina. OBJECTIVE: As all Indonesian HIV patients display high levels of CMV replication, we evaluated whether TNF block genotypes alter markers of their burden of CMV and/or associate with retinitis. METHODS: We assessed 79 consecutive HIV patients beginning ART, 25 HIV patients with a history of CMV-retinitis and 63 healthy adults. HIV RNA, CD4 T-cell counts, CMV-reactive antibody and CMV DNA were measured and alleles of TNFA-308, BAT1(intron 10) and TNFA-1031 (rs1799964) were determined. RESULTS: TNFA-308 and BAT1(intron 10) were in complete linkage disequilibrium. Patients carrying minor alleles at both loci had higher levels of CMV-reactive antibody after one month on ART (p=0.01), but not at other time points spanning 1 year on ART. 50% of patients had detectable CMV DNA before ART, irrespective of TNF block genotypes. However, the TNFA-308*A/- BAT1(intron 10)*C haplotype was more common in CMV-retinitis patients than other patients or healthy controls (p<0.01). CONCLUSION: The TNFA-308*A/BAT1(intron 10)*C haplotype appears to affect CMV-induced pathology rather than CMV replication.