High CD4 nadir implies better control of HIV provirus in patients on antiretroviral therapy
Presenter: Chuen-Yen Lau, MD, MPH, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Several cellular immune subsets correlate with HIV persistence in people living with HIV (PLWH) on long-term antiretroviral therapy (ART).
From multimodal statistical analyses of peripheral blood mononuclear cell samples of 74 PLWH who were virally suppressed on ART for at least 3 years, HIV proviral populations were found to vary in size and composition after long-term ART. Nadir CD, memory and effector memory CD8 cells, and duration of infection correlated with proviral population sizes, according to investigators led by Chuen-Yen Lau, MD, MPH, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
A higher nadir CD4 in PLWH may indicate better immune reserve and ability to control provirus.
“After initial infection, HIV persists as an integrated DNA provirus. This is the major barrier to scalable HIV cure,” she said. “The provirus can be nondefective or defective. Both nondefective and defective provirusus reportedly cause immune activation. In combination with individual factors, this immune activation can result in long-term morbidity and mortality. We hypothesized that an analysis of clinical, viral, and immune characteristics will identify factors associated with HIV persistence.”
TOf participants, mean participant age was 50 years, and mean duration of infection was 17.2 years (range 3.9 to 34.2). Peripheral blood mononuclear cells were obtained by phlebotomy or pheresis. DNA values were available for all participants; RNA values were available for 60 of the 74 participants.
Knowing that the HIV genome has two flanking long terminal repeat (LTR) sequences and an internal gag sequence, samples were analyzed for cell-associated LTR and gag DNA and RNA using multiplex droplet digital polymerase chain reaction. A ratio of two LTRs to one gag was expected for nondefective proviruses and a higher ratio for defective proviruses. CD4 and CD8 lymphocyte subsets were also assessed by flow cytometry. Multimodal statistics were applied to identify associations. A total of 24 statistical tests were used, including linear, parametric and nonparametric correlation, regression, and classification, “with the idea that associations identified as significant in many tests likely represent robust correlates,” noted Dr. Lau.
When looking at correlates of HIV gag DNA levels, nadir CD4 correlated negatively in 21 models, “which makes sense because a higher nadir should result in better provirus control,” continued Dr Lau.
Memory and effector memory CD8 cells had significant positive association in 15 and 14 models, respectively, consistent with antigen-specific memory CD8 cells being stimulated by nondefective genomes. Minimum duration of infection was significantly positively associated in 13 tests, consistent with worse control with longer infection.
In assessing correlates of gag transcription, natural killer (NK) cells were found to have significant positive association in 13 tests, suggesting that the provirus may stimulate innate immunity. Age had significant negative association in 20 tests implying a proxy for ART duration.
The ratio of gag RNA to gag DNA was low in most participants, suggesting that many nondefective proviruses are not transcribing.
“Most interestingly, levels of transcription correlated with natural killer cell activity; perhaps proviral activity drives innate immune activation and NK cells are sensing HIV RNA-containing cells,” said Dr. Lau. “We will continue our analysis using comprehensive statistical approaches to further explore the role of innate immunity and other potential correlates with the long-term goal of supporting HIV cure efforts.”
Disclosure
Dr. Lau has nothing to disclose.