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, β-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.
Highlights
Human immunodeficiency virus type 1 (HIV-1) induces a chronic infection culminating in the development of an acquired immunodeficiency syndrome, it is recognized that critical damage to the host immune system is mediated during the acute phase of infection, when an exponential burst of viral replication takes place, associated with massive depletion of the central memory CD4+ T cell pool [1,2]
Despite a tremendous effort to develop a cure or a vaccine that confers protection against human immunodeficiency virus (HIV-1) infection, this has not been achieved in a satisfactory manner to date
Recent research efforts have suggested that the earliest immune responses activated after exposure to the virus have an influence on virus spread, containment and disease progression
Summary
Human immunodeficiency virus type 1 (HIV-1) induces a chronic infection culminating in the development of an acquired immunodeficiency syndrome, it is recognized that critical damage to the host immune system is mediated during the acute phase of infection, when an exponential burst of viral replication takes place, associated with massive depletion of the central memory CD4+ T cell pool [1,2]. Adaptive responses are known to play an important role in containment of the acute burst of viral replication in AHI [3], but events in the earliest stages of infection are likely to be heavily influenced by components of the innate immune system [3]. These include cellular determinants of the efficiency of viral entry into and replication within host cells such as the CCR5-delta allele, CCR2, CCL5 (RANTES), CX(3)CR1, CXCL12, or TRIM5, all of which can influence host resistance or susceptibility to HIV infection [3]. Genetic studies have helped to cast light on the in vivo importance
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