Virological and immunological characteristics of HIV treatment failure.

BACKGROUND: Resistance to antiretroviral treatment is prevalent. There is limited knowledge of the determinants of disease evolution in subjects infected with multidrug-resistant HIV (MDR-HIV). METHODS: Infectivity, replication, chemokine receptor usage, and env, gag, protease and reverse transcriptase sequence analysis was performed for MDR-HIV isolates from 14 HIV-infected individuals and compared to wild-type HIV isolates from individuals naive to antiretroviral treatment. Expression of CD45RO/RA, Ki67 and interferon-gamma and CD4 proliferative response to various antigens was determined for individuals infected with MDR-HIV and compared to that in individuals with optimal suppression of viral replication. RESULTS: Infectivity and replication are diminished for various MDR-HIV isolates, usually in the context of an increase in CD4 and CD4+CD45RA+ T-cell counts. However, a number of MDR-HIV isolates are associated with high in vivo viraemia and pronounced immunosuppression, and display in vitro levels of infectivity and replication comparable to those of wild-type strains. No specific genetic sequence or chemokine receptor usage predicted the fitness of an MDR isolate. CONCLUSIONS: Despite the biological diversity of resistant viruses and the range of host responses observed, our descriptive analysis indicates that viral factors play a role in determining the degree of immune damage observed in the context of MDR-HIV infection.

Influence of cortisone and cyclophosphamide on xanthine oxidase bacterial activation.

The xanthine oxidase increase in mice liver as response to infection was studied as a possible parameter useful for a better understanding of theimmunosuppression due to cyclophosphamide and cortisone. An impact of cortisone but not of cyclophosphamide on this mechanism was found; this may be useful in order to discriminate between the two different types of immunosuppressive drugs.

Xanthine oxidase activation in animal liver during infectious processes. Short communication.

A relevant increase in xanthine oxidase in the liver was constantly found in the couse of the study of enzyme variations in infected mice. This effect seems to be due to bacterial toxins and not related with microbial pathogenicity. Xanthine oxidase is suspected to play a role in host defence mechanisms.

Degeneracy and additional alloreactivity of drug-specific human alpha beta(+) T cell clones.

It has been well established that T cells can recognize small mol. wt compounds such as drugs. Results from previous studies revealing a high heterogeneity and cross-reactivity of drug-specific T cell clones (TCC) in individual patients prompted us to analyze the degeneracy of drug-reactive TCR in detail. Hence, we analyzed the MHC restriction pattern of a panel of 100 drug-specific TCC isolated from different drug-allergic donors. We found that 28 of the tested clones showed an MHC allele-unrestricted drug recognition. Most of these clones were at the same time highly drug specific, i.e. they could only be stimulated by the original drug and not by any drug derivatives. In contrast, TCC with the ability to interact with different drug derivatives displayed a clearly MHC allele-restricted drug recognition. Therefore, we concluded that the TCR of these clones is mainly interacting with side chains of the appropriate drug molecules and hence able to tolerate alterations in the MHC molecule. Moreover, we tested all clones for additional alloreactivity and found that 27 clones could be stimulated by a self-MHC--peptide--drug complex as well as by a non-self-MHC--peptide complex. This cross-reactivity with allogeneic MHC molecules was substantially higher in drug-specific TCC compared to tetanus toxoid-specific clones from the same donors. This suggests that from the point of view of drug-specific TCR, non-self-MHC--peptide complexes have a higher incidence to mimic the 'original' self-MHC--peptide-drug complex and this may occur for TCR recognizing self-MHC--pathogen-derived peptide complexes. Finally, the biological functions of bispecific TCC were not influenced by the nature of the stimulating ligand. Both drug as well as allogeneic stimulation led to similar reaction patterns in the analyzed TCC.