is Viral Fitness?
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.
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.
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.
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.
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.
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
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.
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).
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.