Differences in Disease Progression in a Cohort of Long-term Non Progressors after More Than 16 Years of HIV Infection

The course of HIV-1 infection varies greatly among infected patients. In a small proportion of individuals (1-5%), HIV-1 seems to be less pathogenic and there is no apparent progression. By definition, these long-term non-progressors (LTNP) remain asymptomatic, with CD4 cell counts > 500 × 10⁶ cells/l and low or undetectable viral load, in the absence of any antiretroviral therapy.

The cause of the lack of progression in these persons is unclear, but it seems to result from the interaction between multiple factors linked to either the virus or the host. The recognition of what factors are the main determinants for protection against HIV-1 disease progression is of great interest, since it may allow new treatment strategies to be designed.

In the present study, the investigators describe the main features of a cohort of LTNP established in 1997 and present longitudinal virologic and inmunologic follow-up for a 6-year period.

Factors Affecting Disease Progression

Among host related factors, some mutations in cellular HIV co-receptor genes have been associated with slower disease progression, as result of an impairment in virus attachment and infectivity.

Disease progression is also influenced by the host immune response. HIV-specific cytotoxic T lymphocytes (CTL) play an important role in the control of virus replication, but their relative contribution in LTNP is still uncertain. The role of a limited immune activation or certain MHC haplotypes in HIV-1 disease progression also remains unclear.

Whether all of these factors may occasionally result in a truly protective status against HIV-1 disease progression, or whether they merely delay disease progression is not known. Evidence in favor of further damage has been reported recently in small series of LTNP followed for long periods of time, but this does not exclude the possibility that infection could be non-pathogenic in some individuals.

Fig. 1. Evolution of mean CD4 cell counts in a cohort of 19 LTNP over 6 years of follow-up. Patients are stratified according to the course of their HIV-1 infection.

Fig. 2. Evolution of plasma viraemia in a cohort of 19 LTNP over 6 years of follow-up. Three viral load determinations per year from each patient are represented. Patients are stratified into two categories, according to their HIV-1 disease progression.

Conclusions

A substantial proportion of LTNP show low-level virus replication and progressive loss of CD4 T cells over time. Progressive immunologic damage seems to be directly associated with some degree of virus replication and T-cell activation.

Discussion

The Δ32-CCR5 allele seems to provide a continuous protective effect during the course of HIV-1 infection, reducing the risk of disease progression by 31% when present in heterozygosity. The authors note that none of the patients presented this allele in homozygosis and only three carried the Δ32 deletion in heterozygosis.

The authors state further, “Since all of them belonged to the SP group, our findings do not support a critical role of CCR5 as cause of LTNP. The protection by the CCR5 delta phenotype is lost when the infecting strain is able to induce syncytia. Interestingly, one of our patients with the Δ32 deletion was the subject who showed a virus with mixed CCR5/CXCR4 tropism. At the time of its appearance, the patient showed a significant CD4 T-cell depletion, perhaps indirectly reflecting a protective effect of Δ32-CCR5.”

The investigators could not find any other virological feature in these LTNP that could distinguish those showing slow progression and those without any progression at all.

In conclusion, the authors write,  “LTNP seem to be a heterogeneous small subset of HIV-1 infected individuals. No unique viral or host factors explain the absence of disease progression. Even very low levels of HIV replication seem to result in progressive CD4 T-cell depletion, although in these patients it may take decades to become manifest. Whether this applies to all LTNP or whether a subset of them will maintain their CD4 T-cell numbers indefinitely is unclear.”

Supported in part by grants from Comunidad Autónoma de Madrid, Asociación Investigación y Educación en SIDA, FIPSE, and Red de Investigación en SIDA (RIS G03/173).

05/24/04

Reference
B Rodés and others. Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection. AIDS 18(8)21:1109-1116. May 21, 2004.