Another question for future HIV eradication studies will be:
does a smaller reservoir of latently infected cells afford a better prospect of
curing HIV infection, and if so, is it possible to limit the size of the
reservoir by treating a person very soon after HIV infection?
Researchers in Thailand have been attempting to do this, by
offering a process of very fast diagnosis and treatment initiation, in a
setting with a high incidence of HIV infection. People who presented to the Thai
Red Cross HIV testing centre in Bangkok were tested for HIV RNA, p24 antigen
and HIV antibodies, using a third-generation enzyme-linked immunosorbent assay (EIA).
Diagnostics were completed within a median of three days,
after which people diagnosed with HIV were asked if they would be willing to undergo
leukopheresis for CD4 cell counting and enumeration of total and integrated HIV
DNA in peripheral blood mononuclear cells (PBMCs). (Integrated HIV DNA
indicates that, in theory, a cell would be capable of producing
replication-competent virus in the future.) Participants were also asked if they
would be willing to undergo sigmoid colon sampling in order to obtain samples
from any potential HIV reservoirs in the gut. A median of two days after
diagnosis, subjects started antiretroviral therapy with a regimen that included
raltegravir in order to achieve very rapid viral load reduction.
The study recruited 75 participants, 91% of them men who have
sex with men. Data were presented on 68 subjects for whom quantification of HIV
DNA had taken place. These included 21 subjects in whom sigmoid biopsies had
also been carried out. Just over one-third (37%) were in Feibig 1 of acute HIV
infection, that is to say, they were HIV RNA positive but negative for p24
antigen and negative for HIV antibody by third-generation ELISA test. The
median time between enrolment and exposure was 15 days in this sub-set of
patients, said Dr Jintanat Ananworanich.
Patients in this sub-set had the lowest HIV DNA levels prior
to treatment; 92% had undetectable integrated HIV DNA in PBMCs and 88% had
undetectable integrated HIV DNA in the sigmoid colon, indicating that a
reservoir of detectable infected cells had not yet been established (although it
should be noted that this study sampled a limited number of cell types).
Patients in Feibig 2 (HIV RNA+, p24+) and Feibig 3 (ELISA+, western blot negative) stages of
acute infection showed substantial reductions in HIV DNA within 12 weeks of
starting antiretroviral treatment, and reached undetectable levels of integrated
HIV DNA in PBMCs by week 24. Seven out of ten patients (3 Feibig 1 and 4 Feibig
2/3 patients) who underwent sigmoid biopsy, and who had detectable integrated
HIV DNA at baseline, had undetectable HIV DNA by week 24 of treatment.
Analysis of CD4 central memory cells (the key reservoir for
infection) showed very limited infection compared to transitional and effector
memory CD4 cells at baseline, and this trend persisted after 24 weeks of
Patients treated early in acute infection, whether in stages
Feibig 1 or 3, showed similar characteristics to 'elite' HIV controllers – a small
or undetectable reservoir of HIV DNA, and a bias towards infection of
transitional and effector cells rather than central memory cells, concluded Dr Ananworanich.
These patients may be ideal candidates for future cure studies which look at
the use of therapeutic vaccines in combination with agents that can deplete the
HIV reservoir. In due course, treatment interruptions might also be attempted in
order to determine whether any of these patients is functionally cured, and if
so, what might be the immunologic correlates of a functional cure.
Dr Katherine Luzuriaga also presented data on the characteristics
of the HIV reservoir after early treatment, this time in five adolescents with
a median age of 16 who had received antiretroviral treatment since soon after
birth (median 2 months of age). It was
impossible to isolate replication-competent HIV DNA from any of these patients,
although proviral DNA was detectable at a low level, and they had no
HIV-specific antibody or CD8+ T-cell responses.
In comparison, four age-matched young people who had begun HIV treatment in later
childhood, and who had sustained undetectable viral load ever since, had detectable
HIV RNA (8 copies/ml) by ultrasensitive assay and HIV antibody and CD8+ T-cell
responses to a broad range of HIV genes, indicating ongoing replication.
Dr Luzuriaga’s group suggested that these young people, like the
acutely infected Thai patients described by Dr Ananworanich, could be “prime
candidates for interventions to achieve functional cure or eradication.”
In contrast, data presented by collaborators from the
University of Pittsburgh and Harvard University, show that in adults treated
with fully suppressive antiretroviral therapy for at least ten years, but
commenced in advanced HIV disease (median CD4 cell count 193 cells/mm3), HIV
DNA declines during treatment, but remains detectable after ten years, with
higher levels correlated with older age and higher baseline viral load. These
findings suggest a much more well-established reservoir of HIV infection in
chronically infected adults.