Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection

Abstract

The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined. Initiation of antiretroviral therapy (ART) at Fiebig stages I to III led to a profound decrease in the frequency of infected cells to nearly undetectable level in all compartments. The rare infected cells that persisted were preferentially found in the lymphoid tissues. Initiation of ART at later stages (Fiebig stages IV/V and chronic infection) induced only a modest reduction in the frequency of infected cells. Quantification of HIV DNA in memory CD4+ T cell subsets confirmed the unstable nature of most of the infected cells at Fiebig stages I to III and the emergence of persistently infected cells during the transition to Fiebig stage IV. Our results indicate that although a large pool of cells is infected during acute HIV infection, most of these early targets are rapidly cleared upon ART initiation. Therefore, infected cells present after peak viremia have a greater ability to persist.

Simian-Human Immunodeficiency Virus SHIV.C.CH505 Persistence in ART-Suppressed Infant Macaques Is Characterized by Elevated SHIV RNA in the Gut and a High Abundance of Intact SHIV DNA in Naive CD4 + T Cells

“…Thus, although the frequency of naïve CD4+ T cells harboring viral DNA is lower than memory CD4+ T cells, the proportion of DNA that represents intact genomes is likely comparable to proportions within memory When measuring levels of replication-competent virus in blood and spleen, we found the spleen was more reflective of pre-ART plasma viral loads, as the two infant macaques with virus levels below the LOD in the spleen QVOA were the same macaques that were refractory to challenges and had dampened plasma viral burden pre-ART. This trend is in line with previous studies implicating lymphoid organs as an early site of infection and a major source of plasma viremia in the absence of ART (64,65). SHIV.C.CH505 persistence was also evaluated in myeloid cells isolated from the brain.…”

Longitudinal analysis of subtype C envelope tropism for memory CD4+ T cell subsets over the first 3 years of untreated HIV-1 infection

“…Given that CM cells represent 23-30% of the total CD4 + T cell pool, this represents a potentially significant source for the establishment of the viral reservoir. Consistent with this, a study of individuals infected with subtype AE found that CM cells were infected at similar frequencies to TM and EM subsets during acute infection [63].…”

The multifaceted nature of HIV latency

“…In line with this observation, initiation of ART in eight individuals at the earliest stage of diagnosable HIV infection (Fiebig I stage) drastically reduced the size of the pool of HIV-infected cells but did not prevent viral rebound upon ART initiation (4,55). A recent and larger study of acutely treated PLHIV revealed that the pool of infected cells rapidly increases and reaches its maximal size in tissues in the first 2 weeks of infection, i.e., before seroconversion (56). Interestingly, the majority of these early targets are rapidly cleared upon ART initiation, suggesting that infected cells have a greatear ability to persist after peak viremia.…”