The success of viral replication also depends on the proteins Nef, Vif, Vpu, and Vpr. These viral products appear to have evolved to defeat host immune mechanisms of viral clearance, as well as antiviral restriction factors—host cellular proteins that function in a cellautonomous manner to inhibit replication of retroviruses. Nef (negative regulation factor) performs multiple critical functions in the viral life cycle. It acts early in the viral life cycle to sustain Tcell activation and the establishment of a persistent state of HIV infection, in part by lowering the threshold for Tcell receptor signaling and downregulating expression of the inhibitory costimulatory receptor CTLA4. Combined, these actions result in greater and more sustained Tcell activation that promotes viral replication. Nef also contributes to immune evasion of infected cells by downregulating expression of MHC class I and class II molecules, making actively infected cells less likely to induce an antiviral immune response or be killed by cytotoxic T cells. Nef also promotes the clearance of surface CD4 molecules, which otherwise would bind to the virion during budding and interfere with virion release. Vif (viral infectivity factor) acts to overcome a cytidine deaminase called APOBEC, which catalyzes the conversion of deoxycytidine to deoxyuridine in reversetranscribed viral cDNA, thereby destroying its ability to encode viral proteins. Vpu (viral protein U) is unique to HIV1 and variants of SIV, and is required to overcome a cellular factor called tetherin, which inserts into both the plasma membrane of the host cell and the envelope of the mature virion to block its release. The function of Vpr (viral protein R) is not fully understood, but it appears to target the restriction factor SAMHD1, a cellular protein that inhibits HIV1 infection in myeloid cells and quiescent CD4 T cells by limiting the intracellular pool of deoxynucleotides (dNTPs) available for viral cDNA synthesis by reverse transcriptase.
13-28 There are several routes by which HIV is transmitted and establishes infection.
Infection with HIV occurs after the transfer of body fluids from an infected person to an uninfected one. HIV infection is most commonly spread by sexual intercourse. Transmission by the exchange of contaminated needles used for intravenous drug delivery or by the therapeutic use of infected blood or blood products also occurs, although the latter route of transmission has largely been eliminated in countries where blood products are routinely screened for HIV. An important route of virus transmission is from an infected mother to child, which can occur in utero, during birth, or through breast milk. Rates of transmission from an untreated infected mother to her child vary (from about 15% to 45%), depending on the viral load in the mother and whether the mother breastfeeds the child, as breastfeeding increases the risk of transmission.
The use of antiretroviral drugs to decrease maternal viral load during pregnancy dramatically reduces the transmission rate to the child (see Section 1335).