The rapid replication of HIV, with the generation of 109 to 1010 virions every day, is coupled with a mutation rate of approximately 3 × 10–5 substitutions per nucleotide per cycle of replication, and thus leads to the generation of many variants of HIV in a single infected patient in the course of a day. This high mutation rate arises from the errorprone nature of retroviral replication and poses a formidable challenge to the immune system. Reverse transcriptase lacks the proofreading mechanisms of cellular DNA polymerases, and the RNA genomes of retroviruses are copied into DNA with relatively low fidelity. Thus, although primary infection is typically established by a single founder virus, numerous variants of HIV, called quasispecies, rapidly develop within an infected individual. This phenomenon was first recognized in HIV and has since proved to be common to all lentiviruses.
As a consequence of its high variability, HIV rapidly develops resistance to antiviral drugs, much as it develops escape mutants that evade Tcell recognition (see Section 1331). When drug is administered, viral variants with mutations that confer resistance emerge and multiply until the previous levels of virus are regained. Resistance to some viral protease inhibitors requires only a single mutation and appears after only a few days (Fig. 13.40); resistance to some inhibitors of reverse transcriptase develops in a similarly short time. In contrast, resistance to the nucleoside analog zidovudine takes months to develop, as it requires three or four mutations in the viral reverse transcriptase. Because of the relatively rapid appearance of resistance to antiHIV drugs, successful drug treatment has typically depended on combination therapy, where
Fig. 13.40 Resistance of HIV to protease inhibitors develops rapidly. after the administration of a single protease inhibitor drug to a patient with HiV there is a precipitous fall in plasma levels of viral Rna, with a half-life of about 2 days (top panel). this is accompanied by an initial rise in the number of CD4 t cells in peripheral blood (center panel). Within days of starting the drug, mutant drug-resistant variants can be detected in plasma (bottom panel) and in peripheral blood lymphocytes. after only 4 weeks of treatment, viral Rna levels and CD4 lymphocyte levels have returned to their original pre-drug levels, and 100% of plasma HiV is present as the drug-resistant mutant.
the chance of simultaneous resistance mutations in multiple HIV proteins is virtually nil. Nevertheless, monotherapy with newer generation antiretroviral agents has proven effective in patients with low viral loads at the onset of treatment.
13-37 Vaccination against HIV is an attractive solution but poses many difficulties.
Although the effectiveness of HAART in restraining HIV replication has profoundly altered the natural history and transmission rates of HIV infection, a safe and effective vaccine for the prevention of HIV infection and AIDS remains the ultimate goal. Ideally, an effective vaccine would elicit both broadly neutralizing antibodies that block viral entry into target cells (that is, antigp120) and effective cytolytic Tcell responses, to both prevent and control HIV infection, respectively. However, no such vaccine has yet been developed, and its attainment is fraught with difficulties that have not been faced in the development of vaccines against other diseases.