Vaccines to Prevent HIV Infection

VACCINES TO PREVENT HIV INFECTION

Despite the many efforts to develop a safe and effective vaccine against HIV infection, the results to date have been negative or controversial at best. Among the reasons for this state of affairs have been the enormous genetic diversity of the virus and the unique features of the HIV envelope protein. One thing we have learned from studies of HIV pathogenesis, however, has been that a vac-cine that induces a strong and specific T-cell immune response in the absence of broadly neutralizing antibodies may blunt initial viremia, even if the infection is not com-pletely prevented. Moreover, they may pre-vent the mass destruction of CD4⁺ T cells, thereby helping to control the infection and prolong disease-free survival.

Before we go to the actual vaccine can-didates, some knowledge of the structure of the HIV is warranted. HIV, together with the simian, feline, and bovine immu-nodeficiency viruses (SIV, FIV, and BIV) all belong to the genus lentevirus in the family of Retroviridae. These viruses char-acteristically produce slowly progressive infections, and the replication depends on an active reverse transcriptase enzyme to transform the viral RNA genome into a proviral DNA copy that integrates into the host cell chromosome. This step provides the enormous genetic diversity of HIV iso-lates in the infected cell, since the reverse transcriptase step is often fraught with errors in replication.

Two types of HIV have been described: HIV-1 and HIV-2, the latter being less virulent, less transmissible, and confined mostly to West Africa. HIV-1 is phylo-genetically close to SIVcpz commensural virus in chimpanzees, which probably arose as a specific transmission event from chimps to humans. However, SIVmac is the etiological agent of simian AIDS and has many of the features of HIV AIDS. HIV-1 is further divided into three major groups: M (major), O (outlier), and N (non M or O). Most of the strains responsible for the AIDS epidemic belong to the M group, and this group has been divided into ten different subgroups known as clades (A–K).

The genome of HIV is a single-stranded positive small RNA molecule, approximately 9.5 kbs in length and encodes the typical retrovirus proteins Gag further divided into M (matrix), C (capsid), and N (nucleocapsid); Pol, cleaved into protease, reverse transcriptase, and integrase; and ENV 160 kD glycoprotein, divided into an external gp120 and a trans-membrane gp41 subunit that together form trimeric spikes on the surface of the virion. Furthermore, the HIV genome encodes a variety of nonstructural proteins such as transactivation protein (Tat) splice regulator protein (Rev) and accessory pro-teins such as Nef, Vpr, and Vpn.