Post-translational intracellular trafficking determines the type of immune response elicited by DNA vaccines expressing Gag antigen of Human Immunodeficiency Virus Type 1 (HIV-1)

ABSTRACT The motifs involved in the various functions of the human immunodeficiency virus type 1 (HIV-1) gp41 cytoplasmic tail (CT), particularly those related to the intracellular trafficking and assembly of envelope glycoproteins (Env) onto core particles, have generally been assessed with a restricted panel of T-cell laboratory-adapted virus strains. Here, we investigated gp41 CT sequences derived from individuals infected with HIV-1 viruses of various subtypes. We identified four patients harboring HIV variants with a natural polymorphism in the membrane-proximal tyrosine-based signal Y712SPL or the Y802W803 diaromatic motif, which are two major determinants of Env intracellular trafficking. Confocal microscopy showed that the intracellular distribution of Env with a mutation in the tyrosine or diaromatic motif differed from that of Env with no mutation in these motifs. Surprisingly, the gp41 CTs of the primary viruses also had differential effects on the intracellular distribution of Env, independently of mutations in the tyrosine or diaromatic motifs, suggesting the involvement of additional determinants. Furthermore, analyses of virus replication kinetics indicated that the effects of mutations in the tyrosine or diaromatic motifs on viral replication depended on the gp41 CT context. These effects were at least partly due to differences in the efficiency of Env incorporation into virions. Thus, polymorphisms in primary HIV-1 gp41 CTs at the quasispecies or subtype level can influence the intracellular distribution of Env, its incorporation into virions, and viral replication capacity.

Download Full-text

Human immunodeficiency virus type 1 subtype C Gag virus-like particle boost substantially improves the immune response to a subtype C gag DNA vaccine in mice

Journal of General Virology ◽

10.1099/vir.0.19396-0 ◽

2004 ◽

Vol 85 (2) ◽

pp. 409-413 ◽

Cited By ~ 21

Author(s):

Ann Jaffray ◽

Enid Shephard ◽

Joanne van Harmelen ◽

Carolyn Williamson ◽

Anna-Lise Williamson ◽

...

Keyword(s):

Immune Response ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Recombinant Baculovirus ◽

Vaccination Strategy ◽

Subtype C ◽

Immunodeficiency Virus ◽

Hiv 1

Human immunodeficiency virus type 1 (HIV-1) subtype C is the predominant HIV in southern Africa, and is the target of a number of recent vaccine candidates. It has been proposed that a heterologous prime/boost vaccination strategy may result in stronger, broader and more prolonged immune responses. Since HIV-1 Gag Pr55 polyprotein can assemble into virus-like particles (VLPs) which have been shown to induce a strong cellular immune response in animals, we showed that a typical southern African subtype C Pr55 protein expressed in insect cells via recombinant baculovirus could form VLPs. We then used the baculovirus-produced VLPs as a boost to a subtype C HIV-1 gag DNA prime vaccination in mice. This study shows that a low dose of HIV-1 subtype C Gag VLPs can significantly boost the immune response to a single subtype C gag DNA inoculation in mice. These results suggest a possible vaccination regimen for humans.

Download Full-text

Endocytic Host Cell Machinery Plays a Dominant Role in Intracellular Trafficking of Incoming Human Immunodeficiency Virus Type 1 in Human Placental Trophoblasts

Journal of Virology ◽

10.1128/jvi.78.21.11904-11915.2004 ◽

2004 ◽

Vol 78 (21) ◽

pp. 11904-11915 ◽

Cited By ~ 30

Author(s):

Gaël Vidricaire ◽

Michael Imbeault ◽

Michel J. Tremblay

Keyword(s):

Human Immunodeficiency Virus ◽

Host Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Intracellular Trafficking ◽

Confocal Imaging ◽

Early Endosomes ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Vertical transmission of human immunodeficiency virus type 1 (HIV-1) is the primary cause of infection by this retrovirus in infants. In this study, we report for the first time that there is a correlation between endocytic uptake of HIV-1 and virus gene expression in polarized trophoblasts. To shed light on the relationship between endocytosis and the fate of HIV-1 in polarized trophoblasts, the step-by-step movements of HIV-1 within the endocytic compartments were tracked by confocal imaging. Incoming virions were initially located in early endosomes. As time progressed, virions accumulated in late endosomes. HIV-1 was also found in apical recycling endosomes and at the basolateral pole. Experiments performed with indicator cells revealed that HIV-1 is recycled and transcytosed. These data indicate that the intracellular trafficking of HIV-1 upon entry into polarized human trophoblasts is a complex process which requires the active participation of the endocytic host cell machinery.

Download Full-text

Human Immunodeficiency Virus Type 1 Infection Induces Cyclin T1 Expression in Macrophages

Journal of Virology ◽

10.1128/jvi.78.15.8114-8119.2004 ◽

2004 ◽

Vol 78 (15) ◽

pp. 8114-8119 ◽

Cited By ~ 30

Author(s):

Li-Ying Liou ◽

Christine H. Herrmann ◽

Andrew P. Rice

Keyword(s):

Immune Response ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Innate Immune Response ◽

Virus Type ◽

Innate Immune ◽

Cyclin T1 ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The Tat protein of human immunodeficiency virus type 1 (HIV-1) is essential for viral replication and activates RNA polymerase II transcriptional elongation through the association with a cellular protein kinase composed of Cdk9 and cyclin T1. Tat binds to this kinase complex through a direct protein-protein interaction with cyclin T1. Monocytes/macrophages are important targets of HIV-1 infection, and previous work has shown that cyclin T1 but not Cdk9 protein expression is low in monocytes isolated from blood. While Cdk9 expression is expressed at a high level during monocyte differentiation to macrophages in vitro, cyclin T1 expression is induced during the first few days of differentiation and is shut off after 1 to 2 weeks. We show here that the shutoff of cyclin T1 expression in late-differentiated macrophages involves proteasome-mediated proteolysis. We also show that cyclin T1 can be reinduced by a number of pathogen-associated molecular patterns that activate macrophages, indicating that up-regulation of cyclin T1 is part of an innate immune response. Furthermore, we found that HIV-1 infection early in macrophage differentiation results in sustained cyclin T1 expression, while infection at late times in differentiation results in the reinduction of cyclin T1. Expression of the viral Nef protein from an adenovirus vector suggests that Nef contributes to the HIV-1 induction of cyclin T1. These findings suggest that HIV-1 infection hijacks a component of the innate immune response in macrophages that results in enhancement rather than inhibition of viral replication.

Download Full-text

Immunostimulatory CpG Motifs Trigger a T Helper-1 Immune Response to Human Immunodeficiency Virus Type-1 (HIV-1) gp160 Envelope Proteins

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.1999.037 ◽

1999 ◽

Vol 37 (3) ◽

Cited By ~ 40

Author(s):

Ludwig Deml ◽

Reinhold Schirmbeck ◽

Jörg Reimann ◽

Hans Wolf ◽

Ralf Wagner

Keyword(s):

Immune Response ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Envelope Proteins ◽

T Helper ◽

T Helper 1 ◽

Immunodeficiency Virus ◽

Hiv 1

Download Full-text

Elicitation of Neutralizing Antibodies with DNA Vaccines Expressing Soluble Stabilized Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers Conjugated to C3d

Journal of Virology ◽

10.1128/jvi.78.9.4710-4719.2004 ◽

2004 ◽

Vol 78 (9) ◽

pp. 4710-4719 ◽

Cited By ~ 59

Author(s):

Joseph F. Bower ◽

Xinzhen Yang ◽

Joseph Sodroski ◽

Ted M. Ross

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Dna Vaccines ◽

Envelope Gene ◽

Immunodeficiency Virus ◽

Monomeric Gp120 ◽

Hiv 1

ABSTRACT DNA vaccines expressing the envelope (Env) of human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting immune responses. Oligomeric or trimeric (gp140) forms of Env that more closely mimic the native proteins on the virion are often more effective immunogens than monomeric (gp120) envelopes. In this study, several forms of Env constructed from the HIV-1 isolate YU-2 (HIV-1YU-2) were tested for their immunogenic potential: a trimeric form of uncleaved (−) Env stabilized with a synthetic trimer motif isolated from the fibritin (FT) protein of the T4 bacteriophage, sgp140YU-2(−/FT), was compared to sgp140YU-2(−) without a synthetic trimerization domain, as well as to monomeric gp120YU-2. DNA plasmids were constructed to express Env alone or fused to various copies of murine C3d (mC3d). BALB/c mice were vaccinated (day 1 and week 4) with DNA expressing a codon-optimized envelope gene insert, alone or fused to mC3d. Mice were subsequently boosted (week 8) with the DNA or recombinant Env protein. All mice had high anti-Env antibody titers regardless of the use of mC3d. Sera from mice vaccinated with DNA expressing non-C3d-fused trimers elicited neutralizing antibodies against homologous HIV-1YU-2 virus infection in vitro. In contrast, sera from mice inoculated with DNA expressing Env-C3d protein trimers elicited antibody that neutralized both homologous HIV-1YU-2 and heterologous HIV-1ADA, albeit at low titers. Therefore, DNA vaccines expressing trimeric envelopes coupled to mC3d, expressed in vivo from codon-optimized sequences, elicit low titers of neutralizing antibodies against primary isolates of HIV-1.

Download Full-text

Evidence for Frequent Reinfection with Human Immunodeficiency Virus Type 1 of a Different Subtype

Journal of Virology ◽

10.1128/jvi.79.16.10701-10708.2005 ◽

2005 ◽

Vol 79 (16) ◽

pp. 10701-10708 ◽

Cited By ~ 77

Author(s):

Bhavna Chohan ◽

Ludo Lavreys ◽

Stephanie M. J. Rainwater ◽

Julie Overbaugh

Keyword(s):

Immune Response ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Major Premise ◽

Global Epidemic ◽

High Risk Women ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT A major premise underlying current human immunodeficiency virus type 1 (HIV-1) vaccine approaches is that preexisting HIV-1-specific immunity will block or reduce infection. However, the recent identification of several cases of HIV-1 reinfection suggests that the specific immune response generated for chronic HIV-1 infection may not be adequate to protect against infection by a second HIV-1 strain. It has been unclear, though, whether these individuals are representative of the global epidemic or are rare cases. Here we show that in a population of high-risk women, HIV-1 reinfection occurs almost as commonly as first infections. The study was designed to detect cases of reinfection by HIV-1 of a different subtype and thus captured cases where there was considerable diversity between the first and second strain. In each case, the second virus emerged ∼1 year after the first infection, and in two cases, it emerged when viral levels were high, suggesting that a well-established HIV-1 infection may provide little benefit in terms of immunizing against reinfection, at least by more-divergent HIV-1 variants. Our findings indicate an urgent need for studies of larger cohorts to determine the incidence and timing of both intersubtype and intrasubtype reinfection.

Download Full-text