HIV functional cure, what can be learned from HIV-2 infection?

HIV provokes a chronic infection that results in the degradation of the immune
system resulting in AIDS, when not treated. In the case of HIV-1 infection this
happens in approximately 99% van de patients. For HIV-2 infections the
percentage of patients that develop AIDS is only 50%. The difference between
progressive and non-progressive HIV-2 infection may be instructional in helping
to understand the pathogenesis, also in relation to HIV-1 infection. This may
help to identify correlates of protection and biomarkers that may be exploited
for treatment and vaccine development.
In a recent review in HIV-1 and HIV-2 chronic infection have been compared (1).
Clinical progression (once it happens) is remarkably similar in HIV-1 and HIV-2
infected patients. Innate immune responses comprise a role for NK cells in
HIV-2 suppression in early asymptomatic infection, but not in progressive HIV-2
and HIV-1 infection (2). Specific immune responses against HIV-2 are more
robust with an important role for polyfunctional Gag-specific CD4 T cell
responses (3). More recently CD8 T cells have also been implicated in the
control of HIV-2 infection (4). A clear difference between the virus is the
presence of the vpx gene in HIV-2 but not HIV-1. Vpx renders myeloid cells
permissive for HIV-2 infection via degradation of SAMHD1 (5). Paradoxally,
this, and the broader co-receptor usage of HIV-2 (see below), extend its
tropism, but do not enhance its relative pathogenicity.
In HIV-1 infection chronic immune activation is thought to drive deterioration
of the host defence (6), which may be the result of microbial translocation. In
non-viremic HIV-2 infection immune activation is low, but increases in with
higher pvl which correlates with increased LPS levels (7). Other explanation
for reduced immune activation in HIV-2 infection have been sought in the action
of Nef. Nef of lentiviruses infecting their natural host, downregulates CD3 and
CD28, thereby preventing cell activation. In HIV-2 this property of Nef is
conserved, but in HIV-1 downregulation has been lost (8).
A cohort of HIV-2 infected patients from Rotterdam has been followed for more
than 20 years (9). Up to date more than ten patients have remained clinically
well, with high stable CD4 counts and low or undetectable plasma viral load
(pvl), without antiretroviral treatment (cART). Other HIV-2 infected patients
had to start cART to prevent progression to AIDS. Thus this cohort provides a
unique opportunity to compare progressive and non-progressive chronic HIV-2
infection.
Previous research from our lab has mainly focussed on the contribution of HIV-2
variants to differences in disease progression. Biological virus clones have
been isolated from both groups (10,11) (METC 2000/221). These viruses have been
characterized for replicative capacity (12), co-receptor usage (13,14), beta
chemokine sensitivity (15), but these properties did not explain differences in
clinical follow-up between these HIV-2 infected patients. Furthermore
Nef-mediated down modulation of CD3 and CD28 correlated with high CD4 T cell
counts in viremic infection, but did not explain why some patient had low or
undetectable viremia (16). In addition we studied Vpx genes from our biological
clones and found no clues for in role in the maintenance of non-progressive
infection (17)

Primary Objective:
Create a complete transcriptome of blood cells from dichotomous HIV-2 infection.

Secondary Objective(s):
Define host factors and pathways that are implicated in the pathogenesis of HIV
infection.
Determine of the mechanisms that guide the dichotomous course of HIV-2
infection and find opportunities for intervention.

This is a research study that uses peripheral blood received through
venipuncture from HIV-infected individuals. In vitro experiments are performed
on RNA isolated peripheral blood cells. Chronically HIV-infected volunteers
will be asked to donate blood either during their scheduled physician visit or
during a scheduled visit for the blood donation. Blood (3 ml) will be collected
in a Tempus tube, containing a chaotropic agent for the instant lysis of all
blood cells and proteins and the stabilization of DNA and RNA. After
cryopreservation RNA will be isolated and hybridized to microarrays for
transcriptome profiling. Transcriptome profiles from progressive and
non-progressive HIV-2 infection will be compared and distinctive markers will
be identified.

The only potential risk of participation in this study is the minor risk
connected to blood donation through venipuncture. There are no direct benefits
for participants in this in vitro research study.