New Insights into the Disease Progression Control Mechanisms by Comparing Long-Term-Nonprogressors versus Normal-Progressors among HIV-1-Positive Patients Using an Ion Current-Based MS1 Proteomic Profiling

For
decades, epidemiological studies have found significant differences
in the susceptibility to disease progression among HIV-carrying patients.
One unique group of HIV-1-positive patients, the long-term-nonprogressors
(LTNP), exhibits far superior ability in virus control compared with
normal-progressors (NP), which proceed to Acquired Immune Deficiency
Syndrome (AIDS) much more rapidly. Nonetheless, elucidation of the
underlying mechanisms of virus control in LTNP is highly valuable
in disease management and treatment but remains poorly understood.
Peripheral blood mononuclear cells (PBMC) have been known to play
important roles in innate immune responses and thereby would be of
great interest for the investigation of the mechanisms of virus defense
in LTNP. Here, we described the first comparative proteome analysis
of PBMC from LTNP (n = 10) and NP (n = 10) patients using a reproducible ion-current-based MS1 approach,
which includes efficient and reproducible sample preparation and chromatographic
separation followed by an optimized pipeline for protein identification
and quantification. This strategy enables analysis of many biological
samples in one set with high quantitative precision and extremely
low missing data. In total, 925 unique proteins were quantified under
stringent criteria without missing value in any of the 20 subjects,
and 87 proteins showed altered expressions between the two patient
groups. These proteins are implicated in key processes such as cytoskeleton
organization, defense response, apoptosis regulation, intracellular
transport, etc., which provided novel insights into the control of
disease progressions in LTNP versus NP, and the expression and phosphorylation
states of key regulators were further validated by immunoassay. For
instance, (1) SAMH1, a potent and “hot” molecule facilitating
HIV-1 defense, was for the first time found elevated in LTNP compared
with NP or healthy controls; elevated proteins from IFN-α response
pathway may also contribute to viral control in LTNP; (2) decreased
proapoptotic protein ASC along with the elevation of antiapoptotic
proteins may contribute to the less apoptotic profile in PBMC of LTNP;
and (3) elevated actin polymerization and less microtubule assembly
that impede viral protein transport were first observed in LTNP. These
results not only enhanced the understanding of the mechanisms for
nonprogression of LTNP, but also may afford highly valuable clues
to direct therapeutic efforts. Moreover, this work also demonstrated
the ion-current-based MS1 approach as a reliable tool for large-scale
clinical research.