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558 ParT fOur Immunological Deficiencies

secretions of infected partners and thereby reduce HIV transmis- Association of certain major histocompatibility complex (MHC)
sion to uninfected partners. The efficacy of the “Treatment as molecules with HIV disease progression is clearly linked to the
Prevention” model is demonstrated in the multinational HIV cytotoxic T-cell responses. Unfortunately, the HIV vaccine-induced
Prevention Trials Network (HPTN 052) clinical trial that examined cytotoxic CD8 T-cell response is insufficient to halt the progression
the effectiveness of ART to prevent the sexual transmission of of acute or chronic HIV disease. This was clearly indicated in
HIV in serodiscordant couples. Serodiscordant couples (1763 the STEP clinical trial, in which the CD8 T-cell effects were the
in number) were randomly assigned to have the infected partner same between HIV-infected vaccinees and sham HIV-infected
either start ART immediately upon enrollment or to defer ART vaccinee controls. Qualities of effector and central memory CD8
until immunological or clinical criteria were met. Of 28 genetically T cells that would be protective include (i) production of cytotoxic
linked infections that occurred during the trial, only 1 infection cytokines (e.g., IFN-γ and IL-2); (ii) rapidly replicating capacity;
occurred in couples assigned to receive immediate treatment, (iii) cytotoxic potential; (iv) high affinity for HIV antigens; (v)
representing a 96% reduction in the risk of HIV transmission. inhibition of HIV replication; (vi) recognition of specific HIV
There were also fewer morbidity and mortality events in the epitopes restricted by protective HLA-B antigens; (vii) central
early-treatment group, suggesting a therapeutic benefit from memory cells with long life spans; and (viii) rapid-attack memory
early treatment as well. cells at mucosal HIV entry sites. A high-level collaboration of
The fundamental paradigm for “Test and Treat” programs is preeminent clinicians and scientists has proposed the modification
the same as that for “Treatment as Prevention” programs. “Test of the partially successful RV144 vaccine with the goal of produc-
and Treat,” however, emphasizes the need for universal voluntary ing a new HIV vaccine that will broadly neutralize HIV and
routine HIV testing and initiating ART immediately in those variants of HIV that emerge under selective pressure (Table 39.3
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found to be positive regardless of CD4 count or viral load. and Table 39.4). These modifications include changes in the
Although the approach remains controversial, with concerns viral epitopes, vaccine adjuvants, and use of a different clade as
regarding drug resistance, increased sexual risk taking in treated the construct of the virus. The goal of this new proposal is to
individuals, and societal cost-effectiveness, this approach may, use the information of many previous HIV trials to produce an
over time, prove to be an effective prevention modality. ideal HIV vaccine that will prevent the spread of HIV infection
in children and adults.
HIV VACCINES: CLINICAL TRIALS Therapeutic Vaccines
Preventive Vaccines A therapeutic vaccine is one in which the vaccine is used after
The production of an effective HIV vaccine has been thwarted infection occurs, aiming to induce antiviral immunity to alter
by the extreme rate of mutation in the virion and the sequestration the course of disease. This would be accomplished by controlling
of the virus in impenetrable reservoirs, predominantly the viremia or reducing the viral set point in infected patients. Primate
nonreplicating CD4 T cell. More than 30 HIV vaccines have models suggest that just such a result is possible, especially with
been tested in human trials, including those with recombinant cellular immunity–inducing vaccines. To date, however, data
env gp120 proteins with adjuvants, HIV DNA plasmids, viral from human studies have not shown any conclusive benefit in
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vectors, and prime-boost designs. These vaccines have, for the using therapeutic vaccines alone. Using a therapeutic vaccine in
most part, yielded disappointing results. Phase III trials of VAX003 combination with ART is another approach currently under
in Thailand (AIDSVAX B/E plus alum) and VAX004 in North investigation. A small study of a therapeutic vaccine in 25
America and Europe (AIDSVAX B/E plus alum) showed no individuals with HIV infection produced a 1 log 10 reduction in
protection against HIV infection. Naked HIV DNA with cytokines viral load compared with placebo-treated individuals with HIV
40
IL-15, IL-12, and chemokine receptor 005 with and without infection. However, HIV disease progression was not seen with
electroporation has not been effective. Pox virus HIV vaccines this therapeutic vaccine in limited follow-up, indicating the need
in the STEP trial of North and South Americas and the Phambili for longer follow-up and larger clinical trials before any measure
trial in South Africa (Ad5-HIV trivalent vaccine) were ineffective of success can be claimed.
in stopping HIV entry or postinfection viremia. However, the
phase III trial RV144 in Thailand (ALVAC-HIV vCP1521 + Future for HIV Vaccines
AIDSVAX gp120 B/E) showed possible protection against HIV The general pessimism that prevailed in the scientific community
infection in heterosexual men and women. 38 after the failure of the STEP vaccine trial is gradually being
In addition to the goal of developing an HIV vaccine that replaced by cautious optimism as a result of the limited success
elicits neutralizing antibodies, the search for a vaccine that of the RV144 clinical trial in Thailand. In addition, there is general
stimulates a protective CD8 cytotoxic T-cell response continues. belief that more basic research exploring vaccine design and

TABLE 39.3 Post rV144 Vaccine Combinations
Improve frequency, Magnitude, and
+
Polyfunctionality of CD4 T-Cell Improve Clade-Specific antibody Improve Durability of antibody
response to HIV-1 Envelope Products responses to gp120 response Through adjuvants
ALVAC (ZM96) +/−DNA Bivalent clade C recombinant gp120 Alum, MF59, AS01 B
NYVAC (ZM96) +/− DNA protein (strains 1086 and TV-1) construct
Ad26+/− MVA gp140 clade C trimeric protein +/− gp140 Alum, AS01 B
mosaic trimeric protein
Taken with permission from Corey et al. Immune correlates of vaccine protection against HIV-1 acquisition. Sci Transl Med 2015; 7: 310rv7. Review.