A Sound Rationale Needed for Phase III HIV-1 Vaccine Trials

We recently isolated from an infant an X4-syncytium-inducing (SI) human immunodeficiency virus type 1 (HIV-1) variant (92US143-T8) that was able to infect CD8؉ lymphocytes independently of CD4. Although it was CD4 independent, the 92US143-T8 isolate also maintained the ability to infect CD4 ؉ cells. In the present study, we investigated the role of CXCR4 in the infection of CD4؉ and CD8 ؉ cells by this primary isolate. The expression of CXCR4 was down modulated in CD8؉ lymphocytes after infection with the 93US143-T8 isolate. Infection of CD8؉ lymphocytes by the 93US143-T8 isolate was prevented by treatment with AMD3100, a specific antagonist for CXCR4, indicating CXCR4-dependent infection. Interestingly, AMD3100 treatment had no inhibitory role in the infection of purified CD4؉ lymphocytes by the same isolate. Furthermore, AMD3100 treatment failed to prevent infection of known CD4 ؉ CXCR4 ؉ T-cell lines (MT-2 and CEM) by the 93US143-T8 isolate. In fact, virus replication in the CD4؉ cells was often enhanced in the presence of AMD3100. Viruses produced from the infected CD4؉ cells in the presence of AMD3100 maintained an unchanged envelope genotype and an SI phenotype. For the first time, these results provide evidence of CXCR4-dependent infection of CD8 ؉ lymphocytes by a primary HIV-1 isolate. This study also shows a different mode of infection for the CD4 ؉ and CD8 ؉ lymphocytes by the same HIV-1 variant. Finally, our findings suggest that a more careful evaluation is necessary before the random use of AMD3100 as a new entry inhibitor in patients harboring SI HIV-1 strains.Although a large number of chemokine receptors that can play critical roles as coreceptors for human immunodeficiency virus (HIV) entry have been identified, primary HIV type 1 (HIV-1) isolates generally use either CXCR4 (X4 strains) or CCR5 (R5 strains) as a coreceptor for infection of CD4 ϩ cells (13). X4 viruses generally appear late in HIV-1 disease, and their appearance is frequently associated with rapid progression to AIDS. However, many HIV-1 isolates that use CXCR4 are also capable of using CCR5 and thus are called dual tropic (R5X4) (6,16,26). X4 and R5X4 viruses are able to infect a larger proportion of the immune cells because, unlike CCR5, the CXCR4 molecules are abundantly expressed on most primary T cells, including the resting T lymphocytes (7). Furthermore, X4 and R5X4 isolates frequently form syncytia in CD4 ϩ cells in vitro, and it is believed that these viruses are primarily responsible for the profound loss of CD4 ϩ cells in the late stages of HIV-1 disease (17). AMD3100, a bicyclam compound, is a specific antagonist for CXCR4 that has emerged as a potent inhibitor of infection by X4 and R5X4 strains (11,15,21,22,28,38). Strong selection pressure against the more pathogenic X4 strains has prompted the suggestion that AMD3100 might be used even in asymptomatic HIV-1-infected patients to prevent the emergence of the more pathogenic X4 viruses (11, 15). We have recently isolated CD4-independent variants from the quasispecie...

Section: Discussionsupporting

confidence: 50%

CXCR4-Dependent Infection of CD8 ⁺ , but Not CD4 ⁺ , Lymphocytes by a Primary Human Immunodeficiency Virus Type 1 Isolate

Zerhouni

Nelson

Saha

2004

“…Whether the immunogenicity of these vaccine candidates will be sufficient to protect humans from HIV-1 remains unknown (5,11,44). The ongoing human phase III trial in Thailand will provide key information in this regard.…”

mentioning

confidence: 99%

Systemic Immunization with an ALVAC-HIV-1/Protein Boost Vaccine Strategy Protects Rhesus Macaques from CD4⁺T-Cell Loss and Reduces both Systemic and Mucosal Simian-Human Immunodeficiency Virus SHIV_KU2RNA Levels

Pal

Venzon

Santra

et al. 2006

Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIV KU2 (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4 ؉ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4 ؉

“…Neutralizing antibodies may be a critical component of immunity required for protection (11,12). However, induction of potent neutralizing antibody responses by means of candidate vaccines has been difficult (10).…”

mentioning

confidence: 99%

Protection of Rhesus Monkeys against Infection with Minimally Pathogenic Simian-Human Immunodeficiency Virus: Correlations with Neutralizing Antibodies and Cytotoxic T Cells

Quinnan

Lewis

et al. 2005

We studied the capacity of active immunization of rhesus monkeys with HIV-1 envelope protein (Env) to induce primary virus cross-reactive neutralizing antibodies to prevent infection following intravenous challenge with simian-human immunodeficiency virus (SHIV). Monkeys were immunized with the human immunodeficiency type 1 (HIV-1) strain R2 Env. Initially, the Env was expressed in vivo by an alphavirus replicon particle system, and then it was administered as soluble oligomeric gp140. Concurrently, groups of monkeys received expression vectors that encoded either simian immunodeficiency virus (