An anti-HIV strategy combining chemotherapy and therapeutic vaccination.

ABSTRACT

Combination chemotherapy using potent anti-retroviral agents has led to significant advances in the clinical management of human immunodeficiency virus (HIV) disease. However, the emergence of multiple drug-resistant mutants, the high need for compliance to adhere to demanding drug-dosing schemes, and the remaining toxic side-effects of drugs make the perspective of life-long treatment unattractive and possibly unrealistic. Therefore, means must be sought to shorten the time span during which treatment is necessary. Such means could be to stimulate an efficient immune response during the period of low virus load and restored CD4 + cell levels, which might be capable of keeping the virus under long-lasting control after treatment is stopped. Here we tested this concept of combined chemotherapy/ therapeutic vaccination in a non-human primate model. Rhesus macaques chronically infected with the chimeric simian/human immunodeficiency virus (SHIV) containing the HIV type 1 (HIV-1) HXBc2 gene for reverse transcriptase (RT) in the genomic background of simian immunodeficiency virus (SIV)(mac239) (RT-SHIV) were treated with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a potent anti-HIV drug. When virus load had decreased significantly, we immunized with SIV genes env, gag/pol, rev, tat, and nef inserted in two different expression vector systems. Four weeks after the second immunization, drug treatment was stopped. Animals were monitored to determine if virus load stayed low or if it increased again to the original levels and if CD4+ T-cell levels remained stable. Humoral and cellular immune responses were also measured. This combined chemotherapy/ therapeutic vaccination regimen induced a significant reduction in the steady-state level of viremia in one out of two chronically infected rhesus macaques. Chemotherapeutic treatment alone did not achieve reduction of viremia in two chronically infected animals. The nature of the immune responses assumed to have been induced by vaccination in one out of the two monkeys remains to be elucidated.