HIV-1 reservoirs are most often studied in peripheral blood (PB), but not all lymphocytes recirculate, particularly T follicular helper (Tfh) CD4 T cells, as well as germinal center (GC) B cells, in lymph nodes (LNs). Ultrasound-guided fine needle biopsies (FNBs) from inguinal LNs and PB samples were obtained from 10 healthy controls (HCs) and 21 HIV-1-infected subjects [11 antiretroviral therapy (ART) naive and 10 on ART]. Tfh cells and GC B cells were enumerated by flow cytometry. HIV-1 DNA and cell-associated (CA) RNA levels in LNs and PB were quantified by real-time polymerase chain reaction. FNBs were obtained without adverse events. Tfh cells and GC B cells were highly elevated in ART-naive subjects, with a median GC B cell count >300-fold higher than HCs, but also remained higher in 4 out of the 10 subjects on ART. GC B cell counts and Tfh cell counts were highly correlated with each other, and also with activated T cells in LNs but not in blood. Levels of HIV-1 DNA and CA RNA viral burden in highly purified CD4 T cells from FNBs were significantly elevated compared with those in CD4 T cells from PB in the ART-naive group, but only trended toward an increase in the ART patients. FNBs enabled minimally invasive access to, and parallel measurement of residual activated T and B cells and viral burden within LNs in HIV-1-infected patients. These FNBs revealed significant GC activity that was not apparent from corresponding PB samples.
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to significant changes to the HIV reservoir and HIV immune responses, indicating that further characterisation of HIV infected patients undergoing HSCT is warranted. Methods: We studied three patients who underwent HSCT after either reduced intensity conditioning or myeloablative conditioning regimen. We measured HIV antigens and antibodies (Ag/Ab), HIV specific CD4+ T cell responses, HIV RNA and DNA in plasma, peripheral blood mononuclear cells (PBMCs), isolated CD4+ T cells from peripheral blood and lymph node cells. The patients remained on ART throughout the follow up period. Results: All patients have been in continued remission for 4–6 years post-HSCT. Analyses of HIV RNA and DNA levels showed substantial reductions in HIV reservoir related measurements in all three patients, changes in immune response varied with pronounced reductions in two patients and a less dramatic reduction in one patient. One patient experienced unexpected viral rebound 4 years after HSCT. Conclusion: These three cases highlight the substantial changes to the HIV reservoir and the HIV immune response in patients undergoing allogeneic HSCT. The viral rebound observed in one patient indicates that replication competent HIV can re-emerge several years following HSCT despite these marked changes.
The dynamics of latent HIV is linked to infection and clearance of resting memory CD4+ T cells. Infection also resides within activated, non-dividing memory cells and can be impacted by antigen-driven and homeostatic proliferation despite suppressive antiretroviral therapy (ART). We investigated whether plasma viral level (pVL) and HIV DNA dynamics could be explained by HIV’s impact on memory CD4+ T cell homeostasis. Median total, 2-LTR and integrated HIV DNA levels per μL of peripheral blood, for 8 primary (PHI) and 8 chronic HIV infected (CHI) individuals enrolled on a raltegravir (RAL) based regimen, exhibited greatest changes over the 1st year of ART. Dynamics slowed over the following 2 years so that total HIV DNA levels were equivalent to reported values for individuals after 10 years of ART. The mathematical model reproduced the multiphasic dynamics of pVL, and levels of total, 2-LTR and integrated HIV DNA in both PHI and CHI over 3 years of ART. Under these simulations, residual viremia originated from reactivated latently infected cells where most of these cells arose from clonal expansion within the resting phenotype. Since virion production from clonally expanded cells will not be affected by antiretroviral drugs, simulations of ART intensification had little impact on pVL. HIV DNA decay over the first year of ART followed the loss of activated memory cells (120 day half-life) while the 5.9 year half-life of total HIV DNA after this point mirrored the slower decay of resting memory cells. Simulations had difficulty reproducing the fast early HIV DNA dynamics, including 2-LTR levels peaking at week 12, and the later slow loss of total and 2-LTR HIV DNA, suggesting some ongoing infection. In summary, our modelling indicates that much of the dynamical behavior of HIV can be explained by its impact on memory CD4+ T cell homeostasis.
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