- Category: Search for a Cure
- Published on Tuesday, 07 August 2012 00:00
- Written by Liz Highleyman
A group of French HIV patients known as the VISCONTI cohort, who started antiretroviral therapy (ART) during the earliest stage of infection, so far appear to be controlling the virus after interrupting treatment, researchers reported at the recent XIX International AIDS Conference (AIDS 2012) in Washington, DC.
One of the factors that makes HIV so difficult to cure is that its genetic material can remain latent inside resting T-cells for years or decades, ready to begin replicating again if the cell are activated.
As cure research comes to the forefront, scientists are revisiting the idea -- popular in some quarters after the advent of HAART -- that starting antiretroviral treatment very early might enable the immune system to gain control of HIV. Some past studies seemed to show that virus disappeared in such patients, but findings have been mixed, and "eradication" has been a moving target as increasingly sensitive assays have been developed.
Charline Bacchus from Pierre and Marie Curie University in Paris presented findings on behalf of the ANRS VISCONTI (Virological and Immunological Studies in CONtrollers after Treatment Interruption VISCONTI) study group during an oral session, and Asier Saez-Ciron from Institut Pasteur gave a summary at the International AIDS Society's HIV cure press conference on July 26.
The VISCONTI analysis included 12 patients (out of a larger cohort of 75) who started potent combination ART with 10 weeks (median 40 days) after HIV infection. Most were infected in the late 1990s, and they sought treatment due to symptoms of acute infection, which only occur in a minority of people. They stayed on treatment for at least 1 year (median 3 years), in contrast to some patients treated during primary infection in other studies who stopped therapy sooner.
The researchers collected and measured resting CD4 T-cells with CD25-CD69-HLADR-CD4 cell surface markers using ultrasensitive real-time-PCR. They categorized T-cells as naive (TN), meaning they were not yet specialized to respond to specific pathogens; transitional-memory (TTM), an intermediate stage of experienced T-cells; central-memory (TCM), long-lived experienced memory cells thought to make up the primary HIV reservoir; and effector-memory cells (TEM).
They then compared immune system characteristics and reservoir distribution of the VISCONTI patients and a group of 8 untreated elite controllers who had undetectable HIV RNA (< 200 copies/mL) without ART on at least 90% of tests over an average of 12 years.
- VISCONTI patients appear to have controlled HIV, with viral load < 50 copies/mL, for a median of 76 months, or more than 6 years, after treatment interruption.
- Activated CD4 T-cells form the VISCONTI patients contained significantly more HIV DNA than resting cells (median 2.7 vs 2.0 log copies/million cells).
- HIV DNA was detected in all cell subsets from all patients, except for naive cells from 8 out of 12 patients, which held 10-fold less virus than all the memory cell subsets (median 1.5 vs 2.4-2.6 log copies/million cells).
- TTM cells were the major subset making up the HIV reservoir, accounting for 56%.
- The elite controller group had similar HIV reservoir characteristics in term of magnitude and distribution.
- However, TTM and TCM cells contributed equally to the reservoir in elite controllers.
- HIV expression in all memory cell subsets from all VISCONTI patients could be induced by T-cell receptor stimulation.
- HIV activation was not possible in naive T-cells, in which no virus was recovered in 6 out of 8 patients.
- VISCONTI participants were more likely to have the HLA B35 gene pattern, but not the protective HLA B27 or B57 patterns seen more often among elite controllers.
"In VISCONTI patients, treatment initiated at primary HIV-1 infection leads, after treatment interruption, to a low -- but inducible -- durable HIV reservoir distributed mainly in short-lived memory CD4 T-cells that mimics the natural distribution observed in elite controllers," the researchers concluded.
Saez-Ciron explained that VISCONTI participants were not, in fact, elite controllers, because they typically had symptomatic primary infection, had much higher viral load over time, and did not have certain featurescharacteristic of elite controllers, such as strong immune responses to HIV antigens. Like controllers, however, they had "very weak" viral reservoirs, which sometimes decreased over time even without ART.
In contrast with normal progressors, a majority of the viral reservoir of VISCONTI participants consisted of short lived T-cells, with long-lived cells "contributing very little," which might enable patients to eliminate HIV sooner. He suggested that 5% to 15% of people with HIV may be able to control the virus after treatment interruption, and researchers are trying to understand why some do and others don’t.
During the discussion period after Bacchus' presentation, Steven Deeks from the University of California at San Francisco noted that in the CASCADE cohort, about 5% of people who started treatment early but then stopped appeared to control HIV -- 5 times higher than the expected number of elite controllers -- suggesting that prompt ART is having an effect.
C Bacchus, L Hocqueloux, V Avettand-Fenoël, et al (VISCONTI and ALT ANRS study groups). Distribution of the HIV reservoir in patients spontaneously controlling HIV infection after treatment interruption. XIX International AIDS Conference (AIDS 2012). Washington, DC, July 22-27, 2012. Abstract THAA0103.
International AIDS Society. New HIV Cure Research Released Today at the XIX International AIDS Conference (AIDS 2012). Press release. July 26, 2012.