An examination of signs of disease progression in survivors of the Sydney Blood Bank Cohort (SBBC)

Birch, M.; Learmont, Jenny; Dyer, Wayne B.; Deacon, Nicholas J.; Zaunders, John; Saksena, Nitin K.; Cunningham, Anthony L.; Mills, John; Sullivan, John S.

doi:10.1016/s1386-6532(01)00198-6

Cited by 62 publications

(52 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One study (Sydney Blood Bank Cohort) analyzed the outcome of eight patients infected after receiving blood transfusions from a single donor infected with a Nef-deleted HIV-1 strain. In this study three of the cohort members remained asymptomatic for at least 14 -18 years (33,34). Other examples of LTNPs infected with Nefdeleted viruses have been reported, suggesting that the absence of Nef may dramatically slow the course of disease (35)(36)(37)(38)(39).…”

mentioning

confidence: 55%

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

Argañaraz

Schindler

Kirchhoff

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

Three viral proteins participate in the down-modulation of CD4 in human immunodeficiency virus type 1 (HIV-1)-infected cells. The underlying mechanisms have been extensively investigated. However, the physiological relevance of this phenomenon remains poorly understood. To address the role of CD4 down-modulation in HIV-1 pathogenesis in vivo, we have characterized the functional properties of nef alleles isolated from seven HIV-1-infected patients at either the stage of AIDS (late alleles) or during the asymptomatic phase of infection (early alleles). HIV-1 variants carrying these nef alleles showed striking differences in CD4 down-modulation, virus infectivity, and replication properties. Infection of T cells with late strains resulted in production of viral particles with enhanced infectivity, as compared with variants carrying early nef alleles. These differences in infectivity were observed only when viruses were produced in cells with high levels of the viral receptor, suggesting a functional link between CD4 levels and the ability of Nef to down-modulate CD4 and to enhance viral infectivity. Similarly, late nef alleles were substantially more active than early nef genes in stimulating HIV-1 replication in high CD4-positive cells, including primary lymphocytes, but not in cells expressing low levels of the CD4 receptor. Single-round assays showed that differences in infectivity between late and early strains are largely reduced when evaluated in target cells with high levels of CD4, suggesting that the inhibitory effect occurs at the entry step. Supporting this, enhanced CD4 down-modulation by late nef alleles was associated with higher levels of envelope incorporation into viral particles, a phenomenon that likely accounted for the augmented infectivity. Our data suggest a mechanistic link between the Nef-mediated CD4 down-modulation and the enhancement of replication in CD4-positive lymphocytes. As progression to disease occurs, HIV-1 Nef variants with enhanced ability to down-modulate CD4 are selected. These strains efficiently overcome the deleterious effects of CD4 and replicate more aggressively in CD4-positive primary lymphocytes. These results highlight the importance of the virus-induced CD4 down-modulation in HIV-1 pathogenesis.

show abstract

mentioning

confidence: 55%

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

Argañaraz

Schindler

Kirchhoff

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…These alterations include deletions in the nef open reading frame and a part of the long terminal repeat (LTR) region as well as duplications and rearrangements within the LTR. Three of the cohort members remained asymptomatic for at least 14 years and are classified as longterm nonprogressors (8), two died of causes unrelated to HIV, and one member with systemic lupus erythematosus died of causes possibly related to HIV (38). Three members had declining CD4 counts and detectable viral loads and therefore are grouped as long-term survivors (8).…”

Section: In Human Immunodeficiency Virus (Hiv)-infected Individuals mentioning

confidence: 99%

“…Three of the cohort members remained asymptomatic for at least 14 years and are classified as longterm nonprogressors (8), two died of causes unrelated to HIV, and one member with systemic lupus erythematosus died of causes possibly related to HIV (38). Three members had declining CD4 counts and detectable viral loads and therefore are grouped as long-term survivors (8). One of these long-term survivors, the original blood donor D36, developed AIDS 18 years after infection with this nef-deleted HIV-1 strain and started highly active antiretroviral therapy in 1999 (38).…”

Section: In Human Immunodeficiency Virus (Hiv)-infected Individuals mentioning

confidence: 99%

“…One of these long-term survivors, the original blood donor D36, developed AIDS 18 years after infection with this nef-deleted HIV-1 strain and started highly active antiretroviral therapy in 1999 (38). Sequence analysis of virus recovered from D36 in 1999 revealed additional deletions in the nef LTR region, thereby reducing the possibility that restored Nef caused the onset of AIDS (8).…”

Section: In Human Immunodeficiency Virus (Hiv)-infected Individuals mentioning

confidence: 99%

See 1 more Smart Citation

Coreceptor Phenotype of Natural Human Immunodeficiency Virus with Nef Deleted Evolves In Vivo, Leading to Increased Virulence

Jekle

Schramm

Jayakumar

et al. 2002

J Virol

View full text Add to dashboard Cite

The Sydney Blood Bank Cohort is a group of patients with slowly progressive infection by a human immunodeficiency virus strain containing spontaneous deletions within the nef long terminal repeat region. In 1999, 18 years after the initial infection, one of the members (D36) developed AIDS. In this work, we used an ex vivo human lymphoid cell culture system to analyze two viral isolates obtained from this patient, one prior to the onset of AIDS in 1995 and one after disease progression in 1999. Both D36 isolates were less potent in depleting CD4؉ T cells than a reference dualtropic, nef-bearing viral isolate. However, the 1999 isolate was measurably more cytotoxic to CD4 ؉ T cells than the 1995 isolate. Interestingly, although both isolates were nearly equally potent in depleting CCR5؉ CD4 ؉ T cells, the cytotoxic effect of the 1999 isolate toward CCR5 ؊ CD4 ؉ T cells was significantly higher. Furthermore, GHOST cell infection assays and blocking experiments with the CXCR4 inhibitor AMD3100 showed that the later D36 1999 isolate could infect both CCR5؉ and CCR5 ؊ CXCR4 ؉ cells efficiently, while infection by the 1995 isolate was nearly completely restricted to CCR5 ؉ cells. Sequence analysis of the V1/V2 and V3 regions of the viral envelope protein gp120 revealed that the more efficient CXCR4 usage of the later isolate might be caused by an additional potential N-glycosylation site in the V1/V2 loop. In conclusion, these data show that an in vivo evolution of the tropism of this nef-deleted strain toward an X4 phenotype was associated with a higher cytopathic potential and progression to AIDS.

show abstract

“…6 Eventually, LTSs exhibit declining CD4 T cell counts with low viral loads and develop immunodeficiency after long asymptomatic periods suggesting that although Nef plays a key role in viral pathogenesis other factors play a role in progression to AIDS. [6][7][8] Rhesus macaques infected with nef-defective molecular clones of simian immunodeficiency virus (SIV) also exhibit significant reductions in pathogenicity. 9 These animals exhibit extended periods of asymptomatic disease, but eventually progress to simian AIDS much like their human counterparts.…”

Section: Introductionmentioning

confidence: 99%

HIV Type 1 Nef Is Released from Infected Cells in CD45⁺Microvesicles and Is Present in the Plasma of HIV-Infected Individuals

Raymond

Campbell-Sims²,

Khan³

et al. 2011

AIDS Research and Human Retroviruses

147

157

View full text Add to dashboard Cite

HIV-1 Nef has been demonstrated to be integral for viral persistence, infectivity, and the acceleration of disease pathogenesis (AIDS) in humans. Nef has also been detected in the plasma of HIV-infected individuals and is released from infected cells. The form in which Nef is released from infected cells is unknown. However, Nef is a myristoylated protein and has been shown to interact with the intracellular vesicular trafficking network. Here we show that Nef is released in CD45-containing microvesicles. This microvesicular Nef (mvNef) is detected in the plasma of HIV-infected individuals at relatively high concentrations (10 ng/ml). It is also present in tissue culture supernatants of Jurkat cells infected with HIV MN . Interestingly, plasma mvNef levels in HIV þ patients did not significantly correlate with viral load or CD4 count. Microvesicular Nef levels persisted in the plasma of HIVinfected individuals despite the use of antiretroviral therapy, even in individuals with undetectable viral loads. Using cell lines, we found Nef microvesicles induce apoptosis in Jurkat T-lymphocytes but had no observed effect on the U937 monocytic cell line. Given the large amount of mvNef present in the plasma of HIV-infected individuals, the apoptotic effect of mvNef on T cells, and the observed functions of extracellular soluble Nef in vitro, it seems likely that in vivo mvNef may play a significant role in the pathogenesis of AIDS.

show abstract

An examination of signs of disease progression in survivors of the Sydney Blood Bank Cohort (SBBC)

Cited by 62 publications

References 10 publications

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

Coreceptor Phenotype of Natural Human Immunodeficiency Virus with Nef Deleted Evolves In Vivo, Leading to Increased Virulence

HIV Type 1 Nef Is Released from Infected Cells in CD45⁺Microvesicles and Is Present in the Plasma of HIV-Infected Individuals

Contact Info

Product

Resources

About

An examination of signs of disease progression in survivors of the Sydney Blood Bank Cohort (SBBC)

Cited by 62 publications

References 10 publications

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

Enhanced CD4 Down-modulation by Late Stage HIV-1 nef Alleles Is Associated with Increased Env Incorporation and Viral Replication

Coreceptor Phenotype of Natural Human Immunodeficiency Virus with Nef Deleted Evolves In Vivo, Leading to Increased Virulence

HIV Type 1 Nef Is Released from Infected Cells in CD45+Microvesicles and Is Present in the Plasma of HIV-Infected Individuals

Contact Info

Product

Resources

About

HIV Type 1 Nef Is Released from Infected Cells in CD45⁺Microvesicles and Is Present in the Plasma of HIV-Infected Individuals