Viral Fitness

What is Viral Fitness?

It has been found that CD4s can remain elevated for many individuals even after viral load increases or rebounds when a person is taking HAART. This was first reported 1-2 years ago by Dr. Steve Deeks. It's generally accepted that remaining on a virologically failing regimen (when viral load is detectable) permits for the accumulation of resistance mutations. This can cause cross-resistance to all drugs and prevent a good response when switching to new drugs. Therefore, I think it's generally accepted today that if a person has good treatment options, he or she should probably switch therapy as quickly as possible. However, newly developing thinking is that--due to CD4s remaining elevated-- if a person with detectable viral load has few or no treatment options, and if viral load is not too high, it is suggested that they may be better off staying on the same therapy, or possibly, it's speculated, some "maintenance" therapy (maintaining mutations and reduced viral replication capacity), until better treatment options are available. Research findings suggest that when resistance mutations are present, a person's virus may not be as harmful because it may not be able replicate as easily. Please read the full report for a better understanding of the underlying concepts.

Viral fitness, or replication capacity (as some say is a more appropriate term), is becoming a focus of attention. It received a good deal of attention at the Resistance Workshop in Sitges, and papers addressing it are reported below. Since you will likely hear increasing information and research focused on this topic, it's important to understand the term and it's clinical applicability.

If CD4s can remain elevated while viral load is detectable or increasing, is it possible that detectable viral load at some reasonably safe level may not matter that much? And, if so, for how long can it be detectable and still be safe, and what level of viral load is safe? These kind of questions raise questions about treatment approaches and guidelines. Maybe some level of detectable viral load is acceptable. Of course, there are many questions regarding safety and long term affects of such an approach. The dogma for several years has been that viral load must be retained to as low a level as possible, preferably <50 copies/ml. This still seems to me to be the preferred goal of therapy. But the ability for CD4s to remain elevated despite detectable viral load raises many questions about how to apply treatment. Since the beginning of the new age of HIV treatment which emerged with the advent of protease inhibitors, and as we acquire increasing experience, treatment is becoming increasingly complex, and maybe new approaches will emerge.

Drug resistance is associated with impaired protease and reverse transcriptase (RT) function and reduced replication capacity. Terri Wrin of Virologic evaluated recombinant viruses from randomly selected patient samples (over 100 samples) submitted to Virologic for phenotypic testing. It's believed that mutations conferring reduced susceptibility also impair viral replication (making a virus possibly less virulent), which can in part be restored by additional compensatory mutations.

Wrin reported that recombinant viruses containing patient derived protease and RT genotypic sequences (mutational patterns) exhibited a broad range of replication capacity (<1% to >100%) when compared to a well characterized reference strain (NL4-3). Wrin reported that a strong correlation was seen between drug resistance and reduced replication capacity. About 85% of the viruses with impaired replication capacity ranging from 1 to 30% of the reference virus showed high phenotypic resistance to antiretroviral drugs. As well, low replication capacity was most often associated with inefficient protease cleavage at several sites in the Gag and Gag-pol polyproteins. Findings indicated that specific mutations impaired cleavage at distinct sites. Wrin reported that mutations D30N, M46I/L, G48V, I54L/A/S/T/V, and I84V correlated strongly with Gag processing defects. She reported that nelfinavir resistant viruses in particular exhibited many protease cleavage defects, and 70% of nelfinavir-resistant viruses showed large reductions in viral replication. Low replication capacity was associated with the number of protease mutations and the presence of either the nelfinavir-resistance mutation D30N alone or L90M in combination with mutations at 20, 46, 73, or 88.

In contrast to findings related to protease, less than 10% of the viruses with low replication capacity displayed a measurable defect in virion-associated RT (less than 20% of wild-type levels) even though RT inhibitor resistance was common. Wrin concluded that resistance to protease inhibitors has a more deleterious effect on viral replication capacity than RT inhibitor resistance. (Resistance Workshop).

Impact of NRTI Mutations on HIV-1 CTL (cytotoxic T-cells) Responses. Assia Samri from the lab of Bridget Autran in Paris reported on a study that I think bears relevance to reduced replication capacity or viral fitness. The purpose of this study was to determine the impact of drug-resistance mutations appearing during NRTI therapy on CTL recognition of the RT enzyme. Two truncated regions of the RT enzyme (RT-1: 1-143; RT-2: 143-293), containing sites of mutations, were tested on Pol-specific CTL lines for 2 patient groups-those treated with mono- or bi-therapy with NRTIs. Mutations M41L, L74V, M184V, and T215Y/F were evaluated in these patients' samples by LiPa. Overall, CTL recognition of wild-type RT-I or RT-2 was comparable in treated and untreated patient samples, but twice as frequent in the samples from patients who had been NRTI treated and had NRTI mutations. RT-1 was recognized in 83% of treated samples containing the M41L and/or L74V, but in only 42% of samples without mutations. Similarly, RT-2 was recognized in 75% of samples containing mutations M184V and/or T215Y/F, but in only 33% of samples without mutations. Amongst those, NRTI-induced mutations enhanced HLA-binding scores in 17 cases (42%), decreased them in 5 cases (12%), while scores remained unchanged in 19 cases (46%). Four of 5 predicted epitopes were recognized at least once in an ELISPOT assay. The frequencies of IFN-y sot-forming cells were between 40 and 270 per 10(6th) PBMC, similar to known CTL epitopes in RT.

Samri concluded that RT mutations induced by NRTIs rarely decrease but can increase the immunogenicity of RT for CTL recognition and might allow a better immune control of resistant viruses (Resistance Workshop).

Correlation Between Viral Fitness & Disease Progression. Eric Arts from Case Western University in Cleveland used a paid assay for viral fitness--measuring viral production after competitive infection of peripheral blood mononuclear cells (PBMCs). Arts compared virus from long-term non-progressors with virus from patients with accelerated progression to AIDS, and found that virus from LTNPs was significantly less fit than the progressors who were either treatment na‘ve or had received double NRTI therapy. Arts reported fitness was strongly correlated with viral load. Arts also concluded that it appears that HIV-1 fitness has a significant impact on disease progression, or at least as consequential as immune response, and that HIV fitness at the point of transmission may also set the stage for subsequent disease progression.