Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection : functional cure

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http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033948

“There may be a window of opportunity during early AHI to intervene and limit CD4 destruction and HIV reservoir formation with the ultimate goal of achieving drug-free remission of HIV. In addition to ART during early Fiebig stages, strategies such as therapeutic HIV vaccines or drugs that target the long-lived cellular reservoir may be necessary to achieve this goal [2], [38] – and persons aggressively treated in these early Fiebig stage infections may be ideal candidates for these interventions…..In order to test for HIV functional cure, treatment interruption will be necessary……..Our study provided evidence that identifying AHI subjects by NAT and sequential EIA, and enrolling them in a study is feasible but technically and logistically challenging and costly[7], [34]. Strengthening the awareness of symptomatic AHI is a less challenging way to identify acute and recent HIV infection making early treatment far more possible……

These findings favor early intervention during AHI to limit immune destruction and HIV reservoir size, and also highlight that immune destruction begins in the earliest days after infection. The latter finding raises concerns regarding the interpretation of these data in the context of protection when considering treatment in later stages of primary infection [10].

It is thought that the early depletion of the GALT, the largest reservoir of CD4+ T cells in the body, is a blow from which the host may not recover even after prolonged ART in the chronic phase of infection [2], [3], [5], [18]. We employed a strategy that blocked HIV at three steps in the viral life cycle -at entry (CCR5 inhibitor), reverse transcription [nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTI) and integration (integrase inhibitor)-and found a marked reduction in viral burden in both gut and plasma HIV RNA and DNA. The extent of HIV DNA reduction after 6 months of therapy exceeded that achieved in chronically infected patients following almost 5 years of conventional three-drug ART. Importantly, in persons whose gut CD4+CCR5+ T cells were depleted, megaHAART was associated with reconstitution of gut CD4+CCR5+ T cells to the normal range.

Background

Limited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy.

Methods and Findings

We prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II, 15 Fiebig III, 2 Fiebig IV) of whom 15 completed 24 weeks of megaHAART (tenofovir/emtricitabine/efavirenz/ralte gravir/maraviroc).Sigmoid biopsies were completed in 24/30 at baseline and 13/15 at week 24.

At baseline, the median age was 29 years and 83% were MSM. Most were symptomatic (87%), and were infected with R5-tropic (77%) CRF01_AE (70%). Median CD4 was 406 cells/mm3. HIV RNA was 5.5 log10 copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/106 PBMC) vs. Fiebig I (8 copy/106 PBMC) (p = 0.01) while the median %CD4+CCR5+ gut T cells was lower in Fiebig III (19%) vs. Fiebig I (59%) (p = 0.0008).

After 24 weeks of megaHAART, HIV RNA levels of <50 copies were achieved in 14/15 in blood and 13/13 in gut. Total blood HIV DNA at week 0 predicted reservoir size at week 24 (p<0.001). Total HIV DNA declined significantly and was undetectable in 3 of 15 in blood and 3 of 7 in gut. Frequency of CD4+CCR5+ gut T cells increased from 41% at baseline to 64% at week 24 (p>0.050); subjects with less than 40% at baseline had a significant increase in CD4+CCR5+ T cells from baseline to week 24 (14% vs. 71%, p = 0.02).

Conclusions

Gut T cell depletion and HIV reservoir seeding increases with progression of AHI. MegaHAART was associated with immune restoration and reduced reservoir size. Our findings could inform research on strategies to achieve HIV drug-free remission.