Continued HIV production from infected macrophage in people on art

The National Institute of Allergy and Infectious Diseases awarded $427,625 to the University of North Carolina at Chapel Hill on June 10, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate mechanisms of ongoing HIV production from infected macrophages in people receiving antiretroviral therapy.

The research examines why some people on antiretroviral therapy experience slower viral decay and delayed virologic suppression despite adherence to treatment. Current understanding holds that initial rapid viral decay results from loss of short-lived infected CD4+ T cells, but slower subsequent decay may result from continued virus production by long-lived HIV-infected macrophages or other mechanisms including ineffective therapy, poor adherence, or drug resistance. Preliminary findings from four study participants who required approximately one year to achieve suppression demonstrated that antiretroviral therapy stopped active HIV-1 replication but infected macrophages continued producing substantial virus. The funded work will expand these observations across a larger patient cohort to characterize the mechanisms generating this persistent viremia, assess its clinical significance, and explore whether ongoing inflammation and neuronal damage occur in affected individuals.

Work is performed in Chapel Hill, North Carolina, with a period of performance through May 31, 2028. The assistance type is a Project Grant (R21 mechanism).

Abstract

After a few weeks of antiretroviral therapy (art), HIV-1 RNA often decays to undetectable levels in blood. The initial decay is typically rapid due to the loss of short-lived, HIV-infected CD4+ t cells, but despite being adherent to art, some people experience a subsequent period of slower decay and may require months to years to reach virologic suppression. The clinical significance of 'slow decay' of HIV-1 RNA after starting art is currently unknown. Assessing the clinical significance of 'slow decay virus' requires identify the mechanisms generating IT and exploring whether there is ongoing inflammation and neuronal damage in these people. There are three potential mechanisms that may generate 'slow decay virus' and they may have very different clinical implications. (1) continued HIV-1 replication due to ineffective art, poor art adherence or drug- resistance. (2) alternatively, art could stop HIV-1 replication, but HIV-1 virions may continue to be produced by HIV-infected CD4+ t cells or (3) macrophage. Virus production without replication that emerges at the time of art initiation is called primary nonsuppresible viremia (NSV) and is mechanistically distinct from secondary NSV observed in people who were previously suppressed. We recently examined four people who required approximately a year to become suppressed and found that art stopped HIV-1 replication, but HIV-infected macrophage continued to produce substantial amounts of virus. These preliminary results are consistent with the long-held belief that after starting art there is a period of rapid viral decay due to loss of HIV-infected CD4+ t cells, but some people have a subsequent period of slower decay due to continued virus production from long- lived, HIV-infected macrophage. The proposed work will expand on these observations and examine the mechanisms generating 'slow decay virus' in a much larger cohort of people on art and explore the clinical implications of having 'slow decay virus' after starting art (i.e. primary NSV). We will use existing, archived, longitudinal blood samples from 99 people in the macs/wihs combined cohort study (mwccs) who did not suppress HIV-1 RNA to undetectable levels by 6 months on art (i.e. people with 'slow decay virus') and samples from 30 people who suppressed virus with typical, rapid kinetics. The proposed experiments will identify the mechanisms generating 'slow decay virus' during art and the clinical implications of 'slow decay virus' (aim 1). In our previous study, we also observed that 'slow decay virus' produced by macrophage often had nonsense/frameshift mutations in the HIV-1 VPR gene that may have promoted continued HIV-1 production from macrophage during art. Specifically, we will explore whether 'slow decay virus' populations produced by macrophage have mutations in VPR or other genes that impact macrophage survival and/or HIV-1 production from infected macrophage (aim 2). We will accomplish these aims using cutting-edge, but highly rigorous approaches. Accomplishing these aims will address clinical concerns about 'slow decay virus', the source of 'slow decay virus' as well as the role that VPR plays in HIV-1 persistence and expression in macrophage during art.