HIV-1 patient assessment and treatment : from multitest to co-receptor (CCR5) gene polymorphism : from Rgp160 immunization to highly active antiretroviral treatment (HAART)

During the last 15 years, understanding of the pathogenesis of HIV- 1 infection and AIDS has developed rapidly. From a mysterious plague-like untreatable disease with unknown cause and transmission route to a well characterized, chronic, manageable, if yet not curable, retroviral infection. Various immunological, virological and clinical parameters as well as responses to rgpl60 immunization and to highly active antiretroviral treatment (HAART) in HIV-1 infected persons have been studied.

Early during the course of infection, immune functions are severely disturbed. We found diminished reactivity to recall antigens in vivo and to HIV-1 antigens in culture. Tuberculin anergy alone was associated with HIV-1 infection. We also found that serum IgG increases over time and may be used as an approximate marker of the length of infection. Oligoclonal bands were typically seen in serum. These findings fit a model of a change in immune balance favouring Th2 over Thl responses.

Although HIV-1 obviously induces strong immune responses, the repetitive escape from both cytotoxic lymphocytes and neutralizing antibodies, and the possibility of hidden epitopes on the viral envelope, gpl60, inspired us to investigate whether immunization with recombinant (r)gpl60 could restore immunological efficiency. Rgpl60 was given with or without zidovudine. New immune responses were found, particularly a very strong CD4+ lymphocyte proliferative response to gpl60, a response that is rarely seen in unimmunized HIV-1 infected persons. The number of peripheral CD4+ Iymphocytes increased after 6 months. There was no increase in viral load. After 5 years immunization there was a trend to more long-term non-progressors in the vaccinated group. Thus long term safety and immunogenicity was shown.

Since a deletion in the CCR5 co-receptor gene (Delta32) has been linked with delayed progression to AIDS we wanted to rule out a disproportionally high prevalence of heterozygosity (Delta32/wt) for the deletion among the vaccinated individuals. We found a Delta32/wt prevalence of 20%, a figure usually found among Caucasians. We also described two patients with Delta32/wt, who were rapid progressors and we could show that those individuals had a shift in viral phenotype from NSI to SI prior to immune deterioration. SI strains can use an alternative co-receptor, the CXCR4. In a larger cross-sectional study we found that disease progression may occur despite Delta32/wt in individuals with SI variants. We could show a positive correlation between SI strains and A32/wt. This could be explained by selection pressure in these individuals or alternatively by an unproportionally high death rate among wt/wt persons with SI virus prior to the study. Thus A32/wt CCR5 does not always protect against disease progression. In a study with HAART, including a protease inhibitor, in unselected patients with advanced immunodeficiency and a substantial history of prior nucleoside analogue experience, we found that 69% had undetectable HIV-1 RNA levels after 12 months treatment. Nucleoside analogue experience and baseline viral load were independent variables in predicting the treatment efficacy after 12 months. Being treatment naive, or having a low baseline viral load predicted long-term treatment response. We found no impact of viral phenotype or CCR5 genotype on the treatment result. Among those investigated, there were no signs of restoration of specific T-cell reactivity to rgpl60 in vitro or to recall antigens in vivo, despite a powerful increase in the number of CD4+ Iymphocytes during HAART.