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Effects of long-term ART initiated during primary HIV infection on reservoir size

Gareth Hardy, HIV i-Base

A study conducted by Maria Buzon and colleagues at Massachusetts General Hospital and Harvard University, sought to determine whether intiation of ART during primary HIV infection could limit the seeding of viral reservoirs. [1]

The research group focused on a group of nine HIV positive people who had begun ART during primary HIV infection, defined as within 6 months of infection. A cohort of 26 people who had initiated ART during chronic infection were used as controls. Both groups had maintained uninterrupted ART for at least ten years. In addition, a cohort of 37 elite controllers who had maintained undetectable viral loads for eight years in the absence of ART were recruited as a reference population. In terms of age, sex, baseline viral load or CD4 counts, or the time to achieve undetectable viral load after ART initiation, there were no differences between the groups that started ART during primary or chronic infection. Despite this, increases in both CD4 T cell counts and the CD4/CD8 T cell ratio were more substantive in the group that initiated ART during primary infection.

Cross-sectional analysis of CD4 T cell HIV DNA levels was performed after ten years ART for the primary and chronic treatment initiation groups and eight years for elite controllers. As expected, elite controllers demonstrated significant reductions in all forms of HIV DNA compared with people who had initiated ART during chronic infection: total HIV DNA (p < 0.0001), 2-LTR HIV DNA (p = 0.015) and integrated HIV DNA (p < 0.0001). Of interest was the contrasting observation that levels of HIV DNA in subjects who initiated ART during primary infection were comparable to those of elite controllers and much lower than those of subjects who initiated ART during chronic infection.

Levels of replication-competent HIV were also determined in the ART-treated cohorts at this time using a previously described viral out-growth assay. Replication-competent HIV was recovered from 3/8 elite controllers, 5/8 people who initiated ART during primary infection, and 9/11 people who initiated ART during chronic infection. The estimated frequency of CD4 T cells bearing replication-competent HIV was significantly higher in people who had initiated ART during chronic infection, compared with elite controllers (p = 0.004). There was also a trend to a higher frequency of CD4 cells bearing replication-competent HIV in people who initiated ART during chronic HIV infection, compared with those that initiated ART during primary infection (p = 0.052).

The researchers then assessed the decay kinetics of the different forms of HIV DNA in CD4 T cells of the different treatment-initiation groups. Comparing HIV DNA levels at year ten of ART with treatment baseline at year zero, subjects who initiated ART during primary infection experienced a mean log10 decay per year of 0.13+/-0.01 (p < 0.00001) in total HIV DNA. The mean log10 decay rate of 2-LTR circles was 0.32+/- 0.03 per year (p < 0.00001) and the mean log10 decay rate of integrated HIV DNA 0.07 +/- 0.01 per year (p < 0.00001).

These decay rates were accelerated in a sub-set of 3 people who initiated ART prior to seroconversion, for all three HIV DNA forms. In contrast, the decay rates of 2-LTR and total HIV DNA in CD4 T cells of subjects who initiated ART during chronic HIV infection were slower. Furthermore, the levels of integrated HIV DNA were not significantly different at year ten compared with year zero for people who initiated ART during chronic HIV infection. In all cases, declines in HIV DNA occurred mostly within the first four years of ART. The authors state that their data suggest the decay kinetics of multiple forms of HIV DNA are faster in people who initiate ART during the earliest stages of infection. As a result, rapid initiation of ART could accelerate the decline of the HIV reservoir in CD4 T cells.

As the HIV reservoir is known to persist to different degrees in specific maturational subsets of CD4 T cells, the researchers next assessed the frequency of total HIV DNA in each maturational subset: naive; central memory; effector memory; terminally differentiated memory; and central memory stem T cells. Levels of total HIV DNA were generally lower in all T cell subsets of subjects who initiated ART during primary infection in comparison to those who initiated ART during chronic infection. However, these reduced levels were only significant for effector memory (p = 0.03) and terminally differentiated memory CD4 T cells (p = 0.004). In analysis of the contribution of CD4 T cell subsets to the total reservoir size, effector memory and terminally differentiated CD4 T cells made a greater contribution to the reservoir in subjects who initiated ART during chronic infection than subjects who initiated ART during primary infection. In contrast, the contribution of the less matured, longer-lived T cell subsets, central memory and central memory stem cells, was greater in people who initiated ART during primary infection than in people who initiated ART during chronic infection. Therefore, while initiation of ART early in HIV infection results in a smaller reservoir size, it includes a greater relative proportion of HIV DNA in less matured, longer living central memory and memory stem T cells.

In conclusion, initiation of ART during primary HIV infection seemed to accelerate viral decay and cause a reduced frequency of infected cells. Despite this, central memory and memory stem T cells made a larger relative contribution to the reservoir in subjects who initiated ART in primary infection, compared with during chronic infection. This suggests that seeding of central memory and memory stem T cells occurs within the first six month of infection, during which these people initiated ART and that they “may represent the population of extremely long-lasting and treatment-refractory component of the viral reservoir that were previously hypothesised” [2].

References:

  1. Buzon M et al. Long-term antiretroviral treatment initiated in primary HIV-1 infection affects the size, composition and decay kinetics of the reservoir of HIV-1 infected CD4 T cells. J. Virol (2014).
    http://jvi.asm.org/content/early/2014/06/24/JVI.01046-14.abstract
  2. Archin N M et al. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A (2012).
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386138/pdf/pnas.201120248.pdf

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