Patients on HAART with Stable Low Viral Load (<10,000 copies/ml) Show Significantly Stronger HIV-specific CD4 and CD8 T-cell Responses Than Both Patients with Full Viral Suppression (<200 copies/ml) and Patients with High Viral Replication (>10,000 copies/ml)

One of the main treatment aims in HIV infection is to drive plasma viral load (VL) persistently below the limit of detection (usually 200 copies/ml), but this goal cannot be achieved in all patients.

Intriguingly, CD4 lymphocyte counts can remain stable, and as previously reported clinical progression can be markedly slowed in some patients with VL values persistently below the higher threshold of 10 000 copies/ml under highly active antiretroviral therapy (HAART).

However, this incomplete viral suppression carries a risk of resistance and treatment failure. The stability of the CD4 cell counts may reflect the reduced viral fitness of the resistant strains in these patients, while the CD4 cell count generally falls during treatment interruption in patients infected by wild-type virus.

The clinical prognosis of patients in whom the CD4 T-cell count increases during antiretroviral therapy is similar regardless of whether there is a detectable VL. This suggests that clinical and/or immunological benefits are possible despite persistence of viral replication in plasma.

It is unclear how stable low-level viral replication and CD4 cell numbers can be maintained under HAART. This study was designed to analyze whether HIV-specific responses in stable partially controlled patients during antiretroviral therapy (ART) differ from those observed in complete HAART failure and whether they contribute to the control of viral load (VL).

Three groups of patients were selected according to plasma HIV RNA levels during 18 months of ART: persistently low VL (LoVL; HIV RNA <10 000 copies/ml; n = 28), undetectable VL (UnVL; HIV RNA <200 copies/ml; n = 29) and high VL (HiVL; HIV RNA >10 000 copies/ml; n = 14).

T-cell responses were studied using lymphoproliferative and interferon (IFN)-[gamma]-ELISpot assays against HIV-p24, -gp160, recall antigens, and 15 pools of HIV-(Gag + RT) peptides.

Results

Frequencies of IFN-[gamma]-producing CD4 T cells against HIV-p24 were higher in LoVL than in UnVL or HiVL groups [median, 131, 47 and 23 spot-forming cells (SFC)/1 x 106 peripheral blood mononuclear cells (PBMC), respectively; P = 0.012 and P = 0.047].

Lymphoproliferative responses to HIV-p24 and recall antigens were similar in LoVL and UnV HIV-specific CD8 T cells were higher in LoVL than in UnVL (1340 versus 410 SFC/1 x 106 PBMC; P = 0.001). They correlated negatively with VL in the LoVL and HiVL (r, -0.393, P = 0.039 and r, -0.643, P = 0.024, respectively) and positively correlated with anti-HIV CD4 cell frequencies in the LoVL group only (r, 0.420; P = 0.026).

Conclusion

The authors conclude, “Persistently low viral replication (<10 000 copies/ml) during ART stimulates high frequencies of HIV-specific CD4 and CD8 T cells compared to full virus suppression or complete ART failure.”

“The association of high anti-HIV activity with large numbers of HIV-specific CD8 T cells contribute to the control of viral replication.”

Discussion

These findings are in keeping with previous reports suggesting that a low replication level of resistant viruses can induce significant HIV-specific CD4 and CD8 T-cell responses as compared with the low CD4 and CD8 T-cell responses to HIV that we detected in patients with full viral suppression during HAART. This latter finding is in accordance with the partial restoration previously reported in such controlled patients.

The patients in this study with stably low viral load on antiretroviral therapy clearly differed from long-term non-progressors (LTNP) who also have strong CD4 and CD8 cell-mediated immunity to HIV.

The authors write, “A threshold VL value of between 200 and 10 000 copies/ml might be necessary to maintain strong CD4 and CD8 T-cell responses during HAART, while not depleting absolute numbers of CD4 T cells or their capacity to respond to recall antigens, as previously suggested by mathematical models.

“This stimulatory effect appears to be specifically mediated by HIV antigens,” they continue, “as similar differences are not observed for other pathogens such as CMV and mycobacteria. The potency of anti-HIV responses obtained with this continuous low level HIV replication is comparable or higher than those observed during treatment interruptions.”  Whether these immune responses to HIV play a role in the stability of both HIV RNA levels and CD4 cell numbers/ratios is a key issue.

Finally, the investigators found that immune defenses against other pathogens were also preserved despite persistent low-level HIV replication. “This is in keeping with the very low incidence of opportunistic infections in patients with CD4 cell repletion despite persistent virus replication on HAART, the researchers observe,

In conclusion, the authors write, “Our results suggest that continuous moderate immunologic stimulation by low-level viral replication helps to maintain potent HIV-specific responses that may play a key role in virus control.”

“These findings may have implications for defining immune correlates of protection. A better understanding of this phenomenon may also help to adequately manage patients with this low level of viral replication in a context of antiretroviral therapy.” [Emphasis added—Ed]

01/10/05

Reference
N Alatrakchi and others. Persistent low viral load on antiretroviral therapy is associated with T cell-mediated control of HIV replication. AIDS 19(1): 25-33, January 3, 2005.