HIV-1 cannot be cured even with decades of antiretroviral therapy. A new cohort study shows that the inducible, replication-competent reservoir does not decline even with prolonged antiretroviral therapy.
Antiretroviral therapy (ART) has helped suppress the HIV-1 virus to almost undetectable levels among those who adhere to the treatment. There are many people living with HIV (PLWH) who have been on ART for years. However, it is known that if one discontinues ART, the virus rebounds. This is because resting CD4+ T cells serve as viral reservoirs.
Nonetheless, studies suggest that, over the years, these reservoirs gradually decline. So, is it possible that in some individuals, these viral reservoirs might decline so much that the virus may fail to rebound on the discontinuation of ART? A study published in the Journal of Clinical Investigation aimed to explore this topic.
HIV Reservoirs Indestructible Over Time
Earlier studies have shown that during the first 3 years of ART, that is, for an initial 44.2 months, HIV-1 virus reservoirs decline by half. Previous studies used the quantitative viral outgrowth assay (QVOA) to measure viral reservoirs and the intact proviral DNA assay (IPDA) to identify proviruses in PLWH.
Hence, the present study used QVOA and IPDA to measure virus reservoirs and proviruses in 42 PLWH. These were individuals enrolled from specialty clinics in Baltimore, San Francisco, Philadelphia, and Toronto who had been on the ART regimen for 22.1 years (mean). The mean age of individuals was 40.8 years. Participants had, on average, 73 viral load measurements during the period of viral suppression. All of them had remarkable results, and thus, out of 3018 total plasma HIV-1 RNA measurements, only three measurements reported a viral load of above 400 copies/mL.
The study found that resting CD4+ T cells carrying inducible proviruses are readily detectable even after prolonged ART using QVOA. Similarly, researchers could readily identify intact proviruses in PLWH on long-term ART. Researchers also noticed a correlation between QVOA and IPDA measurements. The study found that the frequency of cells with inducible, replication-competent proviruses seems to fall for about the first 7 years while on ART. However, after that, levels either stabilize or even begin to increase. Hence, proviral inducibility does not decrease substantially in PLWH even after prolonged ART.
The Bottom Line
The study demonstrated that although there is an initial decline in the viral reservoirs after initiation of ART in PLWH, this decline only contifnues for a few years. After the initial decrease, there is no further decline, and there may be a slow increase in the inducible, replication-competent reservoir size. This study confirms that reservoirs are well-maintained even after 2 decades of treatment, which remains a major barrier to HIV-1 cure.
Source:
McMyn, N. F., Varriale, J., Fray, E. J., Zitzmann, C., MacLeod, H. J., Lai, J., Singhal, A., Moskovljevic, M., García, M. M., Lopez, B., Hariharan, V., Rhodehouse, K., Lynn, K., Tebas, P., Mounzer, K., Montaner, L. J., Benko, E., Kovacs, C., Hoh, R., . . . Siliciano, J. M. (2023). The latent reservoir of inducible, infectious HIV-1 does not decrease despite decades of antiretroviral therapy. Journal of Clinical Investigation, 133(17). https://doi.org/10.1172/jci171554
