Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.
Abstract
The earliest immune responses activated in acute human immunodeficiency virus type
1 infection (AHI) exert a critical influence on subsequent virus spread or containment.
During this time frame, components of the innate immune system such as macrophages
and DCs, NK cells, beta-defensins, complement and other anti-microbial factors, which
have all been implicated in modulating HIV infection, may play particularly important
roles. A proteomics-based screen was performed on a cohort from whom samples were
available at time points prior to the earliest positive HIV detection. The ability
of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1
replication was analyzed using in vitro PBMC and DC infection models. Analysis of
unique plasma donor panels spanning the eclipse and viral expansion phases revealed
very early alterations in plasma proteins in AHI. Induction of acute phase protein
serum amyloid A (A-SAA) occurred as early as 5-7 days prior to the first detection
of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels.
Furthermore, a proteolytic fragment of alpha-1-antitrypsin (AAT), termed virus inhibitory
peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP
have anti-viral activity in vitro and quantitation of their plasma levels indicated
that circulating concentrations are likely to be within the range of their inhibitory
activity. Our results provide evidence for a first wave of host anti-viral defense
occurring in the eclipse phase of AHI prior to systemic activation of other immune
responses. Insights gained into the mechanism of action of acute-phase reactants and
other innate molecules against HIV and how they are induced could be exploited for
the future development of more efficient prophylactic vaccine strategies.
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Barton Ford Haynes
Frederic M. Hanes Distinguished Professor of Medicine
The Haynes lab is studying host innate and adaptive immune responses to the human
immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the
enabling technology to make preventive vaccines against these three major infectious
diseases. Mucosal Immune Responses in Acute HIV Infection The Haynes lab is working
to determine why broadly neutralizing antibodies are rarely made in acute HIV infection
(AHI), currently a major obstacle in the de

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