One of the earliest antiviral defense mechanism is the induction of interferon (IFN) synthesis. “Danger” sensing systems (Toll-like-receptors [TLR], RIG-I-like-receptors) converge in activating the synthesis of type I IFN (, [7
]). IFNs curb viral replication by a variety of mechanisms, including the shut-down of protein synthesis and the degradation of foreign nucleic acids [7
]. Once produced, IFNα/β bind to the IFNAR1 receptor of the same or neighboring cells and initiate a signaling cascade resulting in the induction of hundreds of IFN stimulated genes (ISG) that constitute the “antiviral state” (, [8
Innate immune mechanisms that may contribute to HIV control
The group of type I IFN inhibits both the early as well as late steps of the HIV-1 life cycle [9
], decreases HIV-1 infection of several cell types, and impairs HIV-1 transmission from dendritic cells (DC) to CD4+ T-cells [10
]. Systemic administration of IFNα reduces HIV-1 plasma viremia [11
] and improves production of antiviral antibodies [12
] but multiple studies also indicate that IFN activity against HIV-1 is transient and/or suboptimal. For instance, HIV cell-to-cell transmission is much less susceptible to IFN inhibition than cell-free viral spread [13
]. Plasmacytoid DC (pDC) are the main natural INFα producers in vivo
], but this DC subpopulation appears depleted in chronic HIV infection [15
]. Viable HIV-infected CD4+ T-cells are excellent inducers of pDC [16
] but the capacity of pDC to produce IFNα is impaired during acute HIV-1 infection, suggesting that these cells have reached a refractory or exhausted state [17
]. This early impairment of IFN responses may contribute significantly to HIV dissemination in progressor patients.
Intrinsic retroviral restriction factors such as TRIM5α, APOBEC3 and Tetherin are constitutively expressed but are also strongly up-regulated in response to IFN in a cell-type dependent manner (, , [18
]). Phylogenetic analyses show that these restriction factors have been under strong positive selection throughout primate evolution, indicative of a continuous evolutionary battle between the host and ancient retroviruses or other parasites [18
]. HIV-1 has developed means to escape most of the human restriction factors: for instance APOBEC3G and Tetherin activities are counteracted the HIV-1 Vif and Vpu proteins, respectively ( [18
]). Tetherin and APOBEC3 molecules prevent viral spread (if left unchecked) while TRIM5α variants with activity against HIV-1 would protect the cell from productive infection (). HIV restriction factors are highly polymorphic, which may contribute to individual variations in susceptibility to HIV. While single nucleotide polymorphisms in TRIM5α [20
], Vif-interacting protein Cullin 5 [21
] and APOBEC3G [18
], have been linked to CD4+ T-cell loss and/or rapid disease progression, these genetic associations need to be replicated in large-scale genomic studies comprising individuals of different ancestry.
List of human restriction factors, their mode of action, the targeted retrovirus as well as the known viral countermeasures.
The clearest implication of a restriction factor in HIV disease progression has emerged from studies of copy number variation in the APOBEC3 locus. A large deletion eliminating the entire coding region of APOBEC3B [22
] was found to be associated with an increased risk of HIV-1 acquisition, accelerated progression to AIDS and higher viral setpoints [23
]. The homozygous deletion of APOBEC3B occurs commonly in East-Asians, Oceanic and Ameri-Indian populations [22
] suggesting that certain populations may be more susceptible to infections with viruses known to be targeted by cytidine deaminases (HIV-1, HBV, HPV, HTLV1). APOBEC3B is expressed constitutively at low level in HIV target cells [24
], but is, in contrast to APOBEC3G, resistant to Vif-mediated degradation [23
]. Higher expression levels of such “HIV resistant” restriction factors, either at baseline or upon IFN induction, could conceivably contribute to HIV control.
HIV particles induce type I IFN responses mainly through the TLR7/8/ pathways [14
]. Chronic IFN production may be deleterious for the infected host in the long-term, because it induces death receptors, increases expression of the HIV coreceptor CCR5 [26
], and contributes to abnormal immune activation. The activation of the TLR7/IFN pathway by HIV in pDC appears to have a lower threshold in women than in men, which may contribute to higher immune activation levels and faster disease progression in HIV infected women [27
]. It is relevant that the IFN response appears swiftly resolved in HIV controllers but not in progressor patients, as demonstrated by ISG expression patterns in whole-genome transcriptome studies [28
]. How HIV controllers achieve optimal IFN responses while limiting IFN-dependent immunopathology remains to be elucidated. It is attractive to speculate that early containment of HIV at mucosal transmission sites by ISGs such as TRIM/APOBEC3/Tetherin creates a window of opportunity for the infected host to mount an efficient adaptive immune response ().
Very early events in HIV control