Another year of the Conference on Retroviruses and Opportunistic Infections (CROI 2016) has come to pass. Here are a few less publicized but important highlights on HIV remission and eradication from this year’s conference.
A Second Berlin Patient?
Several attempts have been made in HIV-positive cancer patients to reproduce the possible eradication of HIV seen in Timothy Ray Brown. There have been past reports of procedures that appeared promising, but eventually viral rebound occurred or the patient succumbed to cancer.
During CROI, researchers in Germany reported the case of a forty-one-year-old man in Düsseldorf who continues to show signs, after 900 days, that HIV may have been eradicated from his body.
HIV-positive since November 2010, the unidentified man was diagnosed with acute myeloid leukemia. Doctors attempted to cure him of both his cancer and HIV with the allogenic (involving cells that are genetically dissimilar and hence immunologically incompatible) transplantation of cells from an individual who possessed the CCR5 delta-32 deletion.
To date no HIV proviral DNA has been found in peripheral blood mononuclear cells, bone marrow, or rectal tissue. HIV-specific antibody responses measured by Western blot are waning.
Even in Timothy’s case, eight years later, there still remains an uncertainty as to whether HIV has been completely eradicated from his body. It certainly is too early to label this case an eradication cure and, as the man is still on ARVs, we can’t call this a functional cure. However, the Düsseldorf man appears to be the most promising case to date similar to Timothy Ray Brown.
Results were presented on a subset of participants from the SPARTAC study who experienced post-treatment control after discontinuing ARVs. The SPARTAC study aimed to identify biomarkers that would indicate post treatment control.
Continued follow-up of 3.5 years identified five African participants who continue to maintain viral loads below 400 copies after discontinuation of ARVs. However, two of the five had undetectable viral loads prior to beginning ARVs, which may indicate that they were elite or viremic controllers.
Previous data from the study found three pre-therapy measurements of T-cell exhaustion biomarkers (PD-1, Tim-3 and Lag-3) that were associated with time to viral rebound. However, they did not appear to be significant in the remaining three Africans though it’s difficult to be sure due to the small sample size.
Use of ATI in Curative Studies
An abstract entitled “Relationship among viral load outcomes in HIV treatment interruption trials” examined the relation between the time to viral load rebound and analytic treatment interruption (ATI) viral set points.
ATI is thought to be the most conclusive means of studying potential cure strategies in clinical trials. A review was conducted in 235 study participants engaged in six AIDS Clinical Trials Groups (ACTG) studies to gain a better understanding of the relationship between viral rebound (VL) and ATI viral set points. Researchers found:
• Overall, viral rebound and ATI viral set points were associated with time to viral rebound.
• There was no significant association between rebound timing and ATI VL set point for those who rebounded in less than twelve weeks.
• VL set points were lower in participants with rebound over twelve weeks and participants treated during early infection.
• Pre-ART VL correlated with set point, though sixty-eight percent of participants had a set point lower than pre-ART VL.
According to researchers, “[t]hese results illustrate complex relationships between post-ATI virologic outcomes and the potential presence of biological factors mediating rebound timing and set point.”
Immunotherapy to Block PD-1
Researchers led by Rama Rao Amara at The Yerks National Primate Research Center and Emory University developed an antibody intended to block the PD-1 molecule in monkey’s infected with SIV. The anti-PD-1 antibody was studied in conjunction with ARVs to determine if it could flush HIV out of viral reservoirs.
PD-1 is a molecule that inhibits immune response during chronic HIV infection. Antibodies that block PD-1 have been shown to restore T-cell function.
A cohort of monkeys was treated with the anti-PD-1 antibody for fourteen days. After the first ten days of treatment, ARVs were added. This cohort exhibited quicker viral suppression than the control group, with an average time to viral suppression of forty-two days verses 140 days in the control group. More active antiviral T cells were seen in the antibody cohort.
Monkeys in a separate cohort who received the antibody in three infusions, with a month between each infusion, experienced very low levels of SIV. Viral rebounds were reported as short-lived.
The researchers concluded: “These results reveal for the first time the potential of PD-1 blockade, both on restoring anti-viral CD8 T cell function, and possibly destabilizing the viral reservoir under ART. They highlight the potential of PD-1 blockade to work synergistically with other therapeutic agents such as vaccines and latency reversing agents to effectively diminish HIV reservoir under ART as a means to establish a functional cure.”
by Jeannie Wraight