Paradoxically Greater Persistence of HIV RNA-Positive Cells in Lymphoid Tissue When ART Is Initiated in the Earliest Stage of Infection

Abstract

Starting antiretroviral therapy (ART) in Fiebig 1 acute HIV infection limits the size of viral reservoirs in lymphoid tissues, but does not impact time to virus rebound during a treatment interruption. To better understand why the reduced reservoir size did not increase the time to rebound we measured the frequency and location of HIV RNA+ cells in lymph nodes from participants in the RV254 acute infection cohort. HIV RNA+ cells were detected more frequently and in greater numbers when ART was initiated in Fiebig 1 compared to later Fiebig stages and were localized to the T-cell zone compared to the B-cell follicle with treatment in later Fiebig stages. Variability of virus production in people treated during acute infection suggests that the balance between virus-producing cells and the immune response to clear infected cells rapidly evolves during the earliest stages of infection. Clinical Trials Registration: NCT02919306.

Keywords: HIV reservoir; acute HIV infection; antiretroviral therapy; in situ hybridization; lymphoid tissues.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Measures of HIV in lymph nodes of the untreated group. HIV RNA in situ hybridization and quantitative image analysis were used to measure the frequency of HIV vRNA+ cells/g lymphoid tissue in those biopsied immediately at the time of diagnosis (A) expressed as vRNA+ cells/g and (B) as vRNA+ cells/million CD4 T cells. C, The relationship between log frequency of vRNA+ cells/g and the log plasma viral load is significant (R2 = 0.301, P < .001, linear regression). Abbreviations: F, Fiebig; vRNA+, virus RNA positive.

Figure 2.

The frequency of vRNA+ cell was significantly higher in people treated during Fiebig 1 than other Fiebig stages. A, The frequency of vRNA+ cells/g of LN tissue in Fiebig 1 compared to the frequency from LN in participants from Fiebig stages 2–5 (P = .03). A multivariable linear generalized estimating equation regression model with independent working correlation was used to compare log base 10 transformed vRNA+ cells/g (measured by RNAscope 2.5) during ART between Fiebig groups (Fiebig 1 vs >1), after adjusting for time on ART and age at biopsy (Supplementary Table 5). B, The frequency of cells/g was converted to frequency per million CD4 T cells in the LN (P = .04) and a similarly constructed model was used for comparing log base 10 transformed vRNA+ cells/million CD4 T cells between Fiebig groups. Results from models unadjusted for other covariates (age at biopsy and time on ART) are also presented as a sensitivity analysis (Supplementary Table 5). Abbreviations: ART, antiretroviral therapy; F, Fiebig; LN, lymph node; vRNA+, virus RNA positive.

Figure 3.

Representative images of lymph nodes from Fiebig 1 at the time of diagnosis (A) and after ART (B) and from Fiebig 3 at diagnosis (C) and after ART (D). A, Scale bar 50 µm. B, C, and D, scale bar 100 µm. Arrows show vRNA+ cells. Abbreviations: ART, antiretroviral therapy; vRNA+, virus RNA positive.

Figure 4.

The percent of vRNA+ cells found in B-cell follicles during ART at Fiebig 1–2, Fiebig 3–5, and in a group of HIV-infected people who started ART in chronic HIV infection (data generated from archived tissues). Adjusted P value = .01 for comparing Fiebig 1–2 to chronic infection. Abbreviations: ART, antiretroviral therapy; vRNA+, virus RNA positive.