Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy

@article{Sigal2011CelltocellSO,
  title={Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy},
  author={Alex Sigal and Jocelyn T. Kim and Alejandro Benjamin Balazs and Erez Dekel and Avi E. Mayo and Ron Milo and David Baltimore},
  journal={Nature},
  year={2011},
  volume={477},
  pages={95-98}
}
Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free… 

Antiretroviral Agents Effectively Block HIV Replication after Cell-to-Cell Transfer

TLDR
Common markers of virus replication may not accurately correlate and measure infectivity or drug efficacy in cell-to-cell virus transmission, recapitulating the efficacy of antiretrovirals incell-free virus infections and in vivo.

HIV: How to escape treatment

TLDR
It is proposed that cell-to-cell spread of virus could be a source of localized and intermittent ongoing replication, which may show little evolution, and which could contribute to replenishment of the virus reservoir and virus persistence.

HIV cell-to-cell spread slows evolution of drug resistance

TLDR
It is found that replacing one infection cycle in experimental evolution with cell-free infection, where the filtered supernatant from infected cells, but not the cellular fraction, is used as the viral source, results in more rapid evolution of resistance.

Combination antiretroviral therapy and cell–cell spread of wild-type and drug-resistant human immunodeficiency virus-1

TLDR
It is shown that combining PIs and RTIs improves the potency of inhibition of HIV-1 and effectively blocks both cell-free and cell–cell spread, and comparison of wild-type and drug- resistant viruses reveals that PI- and RTI-resistant viruses have a replicative advantage over wild- type virus when spreading by cell– cell means in the presence of cART.

Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells

TLDR
If the variable effects of antiviral drugs on cell-to-cell virus dissemination of HIV-1 do indeed impact on viral replication and maintenance of viral reservoirs this is likely to be influenced by the antiviral drug class, since PIs appear particularly effective against both modes of HIV -1 spread.

Exploring the Impact of Antiretroviral Drugs on the Cell-to-Cell spread of HIV-1

TLDR
A better understanding of the impact of antiretroviral therapy on cell-to-cell spread of HIV-1 is provided and within reason, bearing in mind the limitations of in vitro models, gives some insight on the possible clinical implications of these observations for current HIV- 1 therapy.

Modeling HIV multiple infection.

Cell-to-cell transfer of HIV infection: implications for HIV viral persistence.

TLDR
Evidence supporting the role for cell-to-cell transmission of HIV in the maintenance of the HIV reservoir will be highlighted and therapeutic considerations and future directions for this area of research will also be discussed.
...

References

SHOWING 1-10 OF 31 REFERENCES

Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy.

The success of combination antiretroviral therapy for HIV-1 infection has generated interest in mechanisms by which the virus can persist in the body despite the presence of drugs that effectively

Multiploid Inheritance of HIV-1 during Cell-to-Cell Infection

TLDR
It is suggested that cell-to-cell infection may explain the high copy numbers of proviruses found in infected cells in vivo and may provide a mechanism through which HIV preserves sequence heterogeneity in viral quasispecies through genetic complementation.

Inefficient Human Immunodeficiency Virus Replication in Mobile Lymphocytes

TLDR
Results indicate that cell-to-cell transfer is the predominant mode of HIV spread and help to explain why this virus replicates so efficiently in lymphoid organs.

Viral Sanctuaries during Highly Active Antiretroviral Therapy in a Nonhuman Primate Model for AIDS

TLDR
This study is the first comprehensive analysis of the tissue and organ distribution of a primate AIDS virus during HAART, demonstrating widespread persistence of residual virus in tissues duringHAART.

Ongoing HIV dissemination during HAART

TLDR
It is proposed that HIV replication occurs in multiple local bursts, associated with immune activation in response to antigens, and current anti-retroviral drugs substantially reduce the size of these bursts and diminish their frequency but fail to abolish them.

Multiplicity of Human Immunodeficiency Virus Infections in Lymphoid Tissue

TLDR
It is found by using mathematical analysis that two mechanisms quantitatively capture the distribution of proviral genomes in HIV-1-infected splenocytes, one where multiple genomes are acquired one at a time in a series of sequential infectious contacts of a target cell with free virions and infected cells, and the other where cell-to-cell transmission of multiple virions or genomes results from a single infectious contact of atarget cell with an infected cell.

Multiple Viral Genetic Analyses Detect Low-Level Human Immunodeficiency Virus Type 1 Replication during Effective Highly Active Antiretroviral Therapy

TLDR
This study demonstrates the variable rates of viral replication when HAART has suppressed plasma HIV-1 RNA for years to a median of <50 copies/ml and that combinations of four or five antiretroviral drugs suppress viral replication even after short-term virologic failure of three-drug HAART and despite ongoing accumulation of drug-resistant mutants.

Modeling Latently Infected Cell Activation: Viral and Latent Reservoir Persistence, and Viral Blips in HIV-infected Patients on Potent Therapy

TLDR
A mathematical model is developed that considers latently infected cell activation in response to stochastic antigenic stimulation, and a phenomenological model is proposed that can robustly generate the multiphasic viral decline seen after initiation of therapy, as well as low-level persistent viremia and intermittent HIV-1 blips.

Dynamics of HIV-1 recombination in its natural target cells

TLDR
Increases in viral load may confer a compounding risk of virus escape by means of recombinational diversification, and a method for measuring HIV-1 recombination directly is developed that employs reporter viruses bearing functional enhanced yellow fluorescent protein and enhanced cyan fluorescent protein genes in which recombination produces a modified GFP gene and GFP fluorescence in the infected cells.

Quantitation of human immunodeficiency virus type 1 infection kinetics

TLDR
Of particular note was the finding that the infectivity of HIV-1 during cell-to-cell transmission is 10(2) to 10(3) times greater than the infectability of cell-free virus stocks, the inocula commonly used to initiate tissue culture infections.