Update from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication
AIDS INFORMATION NEWSLETTER
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].
This work suggests that the enzymatic activity of protease
resistant to indinavir requires compensatory mutations in the
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,
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
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,
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
Back | Next
Table of Contents