Effect of cytomegalovirus co-infection on normalization of selected T-cell subsets in children with perinatally acquired HIV infection treated with combination antiretroviral therapy

Abstract

Background: We examined the effect of cytomegalovirus (CMV) co-infection and viremia on reconstitution of selected CD4+ and CD8+ T-cell subsets in perinatally HIV-infected (PHIV+) children ≥ 1-year old who participated in a partially randomized, open-label, 96-week combination antiretroviral therapy (cART)-algorithm study.

Methods: Participants were categorized as CMV-naïve, CMV-positive (CMV+) viremic, and CMV+ aviremic, based on blood, urine, or throat culture, CMV IgG and DNA polymerase chain reaction measured at baseline. At weeks 0, 12, 20 and 40, T-cell subsets including naïve (CD62L+CD45RA+; CD95-CD28+), activated (CD38+HLA-DR+) and terminally differentiated (CD62L-CD45RA+; CD95+CD28-) CD4+ and CD8+ T-cells were measured by flow cytometry.

Results: Of the 107 participants included in the analysis, 14% were CMV+ viremic; 49% CMV+ aviremic; 37% CMV-naïve. In longitudinal adjusted models, compared with CMV+ status, baseline CMV-naïve status was significantly associated with faster recovery of CD8+CD62L+CD45RA+% and CD8+CD95-CD28+% and faster decrease of CD8+CD95+CD28-%, independent of HIV VL response to treatment, cART regimen and baseline CD4%. Surprisingly, CMV status did not have a significant impact on longitudinal trends in CD8+CD38+HLA-DR+%. CMV status did not have a significant impact on any CD4+ T-cell subsets.

Conclusions: In this cohort of PHIV+ children, the normalization of naïve and terminally differentiated CD8+ T-cell subsets in response to cART was detrimentally affected by the presence of CMV co-infection. These findings may have implications for adjunctive treatment strategies targeting CMV co-infection in PHIV+ children, especially those that are now adults or reaching young adulthood and may have accelerated immunologic aging, increased opportunistic infections and aging diseases of the immune system.

Fig 1. Mean T-cell Phenotype Percentages by CMV Status and Week.

This figure shows trends in reconstitution of selected CD4+ and CD8+ T-cell phenotypes in response to cART by cytomegalovirus (CMV) co-infection status and study week in the ACTG 366. Left column (top to bottom): The rate of change in the percentage of activated CD4+ T-cells (i.e., CD4+CD38+HLA-DR+%) was marginally significant by the CMV status. Neither naïve (i.e., CD4+CD62L+CD45RA+% and CD4+CD95-CD28+%) or terminally differentiated effector CD4+ T-cells (i.e., CD4+CD95+CD28- and CD4+CD62L-CD45RA+) were significantly affected by CMV co-infection or viremia status. Right column (top to bottom): The rate of change in the percentage of activated CD8+ T-cells (i.e., CD8+CD38+HLA-DR+%) was not significantly affected by the CMV status. The increase in both CD8+ naïve subsets (i.e., CD8+CD62L+CD45RA+% and CD8+CD95-CD28+%) in response to cART was significantly slower in CMV+ viremic and aviremic groups compared to CMV-naïve group. The decrease in one of the terminally differentiated effector subsets of CD8+ T-cells (i.e., CD8+CD95+CD28-%) in response to cART was significantly slower in CMV+ viremic and aviremic groups compared to CMV-naïve group. The rate of change in the percentage of the other terminally differentiated effector CD8+ subset (i.e., CD8+CD62L-CD45RA+) in response to cART was not significantly affected by CMV co-infection or viremia status.

Fig 2. Effect of CMV-specific cell-mediated immunity (CMI) on normalization of selected T-cell subsets in CMV+ participants.

This figure shows the relationship between CMV-specific cell-mediated immunity (CMI) and changes over time in three selected CD8+ T-cell subsets in response to cART among 103 eligible participants with available CMV CMI results. In linear mixed effects models, CMV CMI+ status was significantly associated with lower mean CD8+CD62L+CD45RA+% (naïve) (p = 0.03) and CD8+CD95-CD28+% (naïve) (p = 0.045), but not with CD8+CD95+CD28-% (terminally differentiated) (p = 0.19).