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Antiretroviral Therapy
(Part XXIV)

Update from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication

November 7, 1997

AIDS Information Center VA Medical Center, San Francisco

Mechanisms of Antiretroviral Resistance

Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its gag substrate cleavage sites

The mechanism of resistance to protease inhibitors may be more complex than initially suspected. HIV-1 protease must cleave various proteins at specific sites. When the protease enzyme "mutates" in response to the selective pressure of an inhibitor, it may no longer be able to adequately cleave HIV-1 proteins. Theoretically, mutations in the cleavage site may allow the "mutant" protease to function more efficiently.

In this study, 6 patients failed indinavir. Sequence analysis showed that these 6 patients rebounded with changes at positions 46, 54, 71, 82, 84 and/or 90. In all 6 patients, there was an identical mutation seen in the gag p7/p1 protease cleavage site.

Site directed mutagenesis studies were performed to determine the relevance of these gag mutations. If mutations at positions 46 and 82 were present in the face of the wild type gag sequences, viral replication was severely hampered. However, if mutations in the p7/p1 cleavage site were present in the gag gene, the "resistant" virus (containing mutations at positions 46 and 82) replicated efficiently [Zhang et al, abstract 19].

Comment: This work suggests that the enzymatic activity of protease resistant to indinavir requires compensatory mutations in the enzyme's substrate.

A unique mechanism for zidovudine-resistance

Zidovudine (AZT) typically selects for the T215Y and M41L mutations. These mutations presumably reduce the ability of AZT to bind to the active site of reverse transcriptase, thus allowing the virus to replicate. Eric Arts and colleagues suggest a novel mechanism of resistance to AZT. Their data indicates that AZT metabolites stimulate reverse transcriptase activity when the T215T and M41L mutations are present. Theoretically, this enhanced activity may allow HIV to overcome the inhibitory effects of AZT and perhaps all reverse transcriptase inhibitors [Quinones-Mateu, abstract 10].

Comment:This intriguing study suggests that AZT metabolites may stimulate reverse transcriptase activity. If true, this could lead to cross-resistance to all reverse transcriptase inhibitors. This may explain the lack of ddI and ddC mutations in patients who fail the combination of AZT plus ddI or AZT plus ddC.

Pathways for zidovudine/lamivudine dual resistance

Zidovudine (AZT) selects for several mutations, including changes at positions 215 and 41. Lamivudine selects for a mutation at position 184. This M184V mutation appears to suppress the effects of 215 and 41, thusallowing continued AZT activity. This observation, confirmed in clinical trials, provides the basis for the popular AZT/3TC combination.

Resistance to the combination of AZT and 3TC can occur. Until recently, the genetic basis for this dual resistance was unknown. This group from Glaxo-Wellcome presented preliminary data suggesting that known polymorphisms at positions 211 and 214 may confer some degree of dual AZT/3TC resistance. A novel mutation atposition 333 (G333E) of the reverse transcriptase gene may also facilitate cross-resistance via a distinct pathway [Kemp, abstract 11].

Comment: Complex patterns involving these mutations, and others, probably provides the genetic basis for dual resistance to AZT/3TC. This study again illustrates the limitations of our current knowledge regarding the genetic basis of drug resistance.

Cross-resistance to HIV-1 protease inhibitors in vitro

Does resistance to one protease inhibitor confer cross resistance to other protease inhibitors? This remains an area of controversy. The cell culture work performed by Ronald Swanstromþs group suggests that resistance to these drugs is a class effect. When low concentrations of indinavir, ritonavir and saquinavir are used in vitro, initial mutations evolve that are similar to those reported before. Cross-resistance is limited under these conditions. When higher concentrations of drug are used, these three inhibitors select for very similar mutation patterns [Smith et al, abstract 15].

Comment: A general theme at the conference was that one protease inhibitor selects for resistance to the entire class of drugs. Swanstromþs in vitro work confirms these in vivo observations, and suggests that each inhibitor selects for very similar mutation patterns. Notably, nelfinavir was not used in this study.

HIV genotyic variation in plasma and vaginal lavages

This study compared the genotype of HIV-1 obtained simultaneously from plasma and vaginal lavages of women on antiretroviral therapy. Eight women were studied. Viral RNA and pro-viral DNA were analyzed. Polymorphic changes at position 214 of the reverse transcriptase gene was found in 8 of 8 blood samples, and 0 of 8 vaginal lavage samples. In a limited number of patients followed over time, antiretroviral mutations evolved in plasma HIV-1 RNA, but not in vaginal lavage fluids [Schinazi et al, abstract 93].

Comment: These preliminary findings indicate that HIV in vaginal secretions is produced locally, and that either (1) antiretroviral therapy has limited efficacy in vaginal fluids, or (2) the primary reservoir of HIV in the vagina is longed lived cellular reservoirs (i.e., macrophages).

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