HIV-1-Specific CD4+ T Cell Responses in Chronically HIV-1 Infected Blippers on Antiretroviral Therapy in Relation to Viral Replication Following Treatment Interruption

Abstract

The impact of transient viral load blips on anti-HIV-1 immune responses and on HIV-1 rebound following treatment interruption (TI) is not known. Clinical and immunological parameters were measured during 40 weeks of antiretroviral therapy (ART) and following TI in an observational cohort of 16 chronically HIV-1-infected subjects with or without observed viral load blips during ART. During therapy, blips in seven subjects were associated with higher anti-HIV-1 (p24) CD4+ T cell lymphoproliferative responses (p = 0.04), without a significant difference in T cell activation or total anti-HIV-1 CD8+ T cell interferon-gamma (IFN-gamma) responses when compared to nine matched non-blippers. Therapy interruption resulted in a significantly higher viral rebound in blippers by 8 week despite retention of higher lymphoproliferative p24 responses (p = 0.01) and a rise in CD3+ T cell activation (p = 0.04) and anti-HIV-1 CD8+ T cell responses in blippers by week 4 when compared to non-blippers. Past week 4 of interruption, therapy re-initiation criteria were also met by a higher frequency in blippers by week 14 (p < 0.04) with no difference between groups by week 24. These data support that blippers have higher anti-HIV lymphoproliferative responses while on ART but experience equal to higher viral rebound as compared to matched non-blippers upon TI.

Influence of Episodes of Intermittent Viremia (“Blips”) on Immune Responses and Viral Load Rebound in Successfully Treated HIV-Infected Patients

“…16 After cART discontinuation, we also found that the detectable group presented a higher viral rebound, similar to the only previous work that explored this issue. 7 These data support the hypothesis that a high level of immune activation (and not the absolute number of CD4 + T cells) is the force that fuels viral replication. These findings could have two possible explanations (or a combination of them).…”

“…12,26,28 Detectable patients showed higher HIV-specific CD8 + T cell responses under cART, as previously described. 6,7,9 Although it has been hypothesized that these responses would help to control viral replication, 8,[29][30][31] we have demonstrated in one previous work 7 that these patients presented a higher viral rebound after cART discontinuation. This apparent paradox could be explained by the existence of parallel dysfunctions in innate immune responses, 32,33 clonal depletion, 34 or impaired CD8 + T cell function.…”

“…On the one hand, patients with EIV present higher levels in both the magnitude and the breadth of total HIV-specific CD8 + and CD4 + T cell responses compared to persistently undetectable patients. [6][7][8][9] These responses could help to control viral replication 8 and they would be associated with higher CD4 + T cell counts 4 without increasing the risk of virological failure. 1,3,4,[10][11][12][13][14] On the other hand, it has also been shown that EIV increases T cell activation and therefore facilitates the extension of HIV infection.…”

“…5,15 Finally, one observational study evaluated the influence of EIV in the control of viral replication after cART interruption, and found a higher viral rebound among patients who had EIV (''blippers''). 7 To explore the influence of EIV on T cell subsets, HIVspecific T cell responses, and viral rebound before and after discontinuing cART, we reanalyzed the data of a prospective study evaluating the influence of vaccination on VL rebound and immune responses, and where immunizations were not associated with an increase in detectable VL.…”

HLA Class I-Restricted T-Cell Responses May Contribute to the Control of Human Immunodeficiency Virus Infection, but Such Responses Are Not Always Necessary for Long-Term Virus Control

“…It has also been suggested that the absence of T-cell responses in ART-suppressed individuals may be due to immunologic damage during previous high-level viremia (46). However, this is unlikely to be the case given that, upon ART discontinuation or failure, HIV-specific T-cell responses return (18,41,44,45).…”