Very Early HIV Treatment May Limit "Seeding" of Latent HIV Reservoirs, Study Finds

Early HIV treatment, specifically during acute HIV infection, can limit the virus from forming HIV reservoirs in central memory CD4+ cells, according to study results presented at CROI 2013 in Atlanta, Ga.

Researchers in Thailand screened 52,767 patients for HIV using both nucleic acid tests (NAT) and enzyme-linked immunosorbent assay (ELISA) tests. Only 89 were identified as having acute HIV infection. Of these, 75 were enrolled in the study within three days and then started on antiretroviral therapy within an additional two days.

Lead author Jintanat Ananworanich, M.D., presented findings on the first 68 participants. The median age was 29 and 91% were men who have sex with men. The median duration of infection at baseline was only 15 days.

The patients were separated into three groups by Fiebig stage:

There were 24 patients characterized as Fiebig 1, meaning they tested positive for HIV RNA within 15 days of infection, but negative for p24 antigen and negative on a third generation ELISA test.

Only 7 patients were characterized as Fiebig 2, meaning they tested positive for HIV RNA and p24 antigen within 20 days of infection, but negative on a third-generation ELISA test.

The majority, 36 patients, were characterized as Fiebig 3, meaning they tested positive for HIV RNA and p24 antigen, as well as positive on a third generation ELISA test, within 25 days of infection, but negative on a Western blot.

At the time of diagnosis, Fiebig 1 patients had the lowest levels of median HIV DNA compared to the Fiebig 2 and 3 groups. "As the Fiebig stage progresses, there's more seeding of the reservoir," Ananworanich stated. Notably, 92% of the Fiebig 1 group had undetectable integrated HIV DNA in their peripheral blood mononuclear cells (PBMCs), compared to 29% of Fiebig 2 and 53% of Fiebig 3.

By week 12 after starting treatment, the median HIV DNA levels of those in the Fiebig 3 group mirrored levels seen in patients who have been on treatment for five years. By week 48, the Fiebig 3 group had HIV DNA levels similar to elite controllers. Interestingly, the Fiebig 1 group had HIV DNA levels similar to elite controllers throughout 96 weeks of treatment. In terms of integrated HIV DNA, 93% of all groups achieved undetectable levels by week 48.

To attempt to determine where HIV established and maintained its reservoirs, the researchers ran additional tests, including leukapheresis, a procedure that separates white blood cells from blood samples. After 24 weeks of treatment, integrated HIV DNA was detected in CD4+ cells, but not PBMCs, B cells or CD8 cells. 

However, even within the CD4+ cell subset, only two out of five patients had detectable levels.

The researchers looked even further into the subsets of memory CD4+ cells to possibly identify the reservoir location. They found that central memory T cells had low infection frequencies when compared to transitional memory and effector memory T cells. 

Anaworanich pointed out that in chronically infected HIV patients, the central memory T cells show higher frequencies of infection and typically rank first or second as a reservoir site. 

Her team's finding that the reservoir in the Thai patients, after early treatment, is actually in the transitional memory and effector memory T cells could lead to new strategies in reservoir eradication, she said.

While these results are promising, Anaworanich noted that the sample size was small and that they had yet to determine the levels of replication-competent virus in these patients. The next steps could include analytical treatment interruption to identify correlates of a functional cure or a therapeutic vaccine.