Myth: HIV is a harmless passenger virus

Fact: Studies in vitro, ex vivo and in vivo all support HIV's ability to deplete CD4+ T-cells.

There are some denialists that argue that HIV does exist but that it is merely a harmless passenger virus and that no evidence exists to claim otherwise. In fact, there are thousands of studies that support the cytopathic properties of HIV. While some aspects of how HIV destroys cells that are not fully understood, that it does so it beyond doubt. This is not unique to HIV, of course, as the effects of many diseases are known despite the mechanisms not being completely elucidated. Some of what is known (and supporting evidence will be cited) is the documented here. Since there are literally thousands upon thousands of papers on HIV, a representative few are cited here. This is by no means an exhaustive list.

Evidence shows us that AIDS the CD4+ T-cell depletion is due to HIV.

This can be observed 1) in vitro (in cell cultures), 2) ex vivo (in tissues removed from animal models or patients), and 3) in vivo both in animal models and in infected individuals.

1) In vitro evidence:

Infectable CD4+ cells in culture, when exposed to HIV, become infected and die. This is not limited to cells naturally expressing CD4 such as CD4+ T-cells. It can be induced artificially, as well. For example, HeLa cells (cervical carcinoma cells) are not normally able to be infected by HIV due to a lack of CD4 expression. However, when the same HeLa cells were forced to express CD4, HIV could and did infect the cells, killing them and forming plaques (regions depleted of cells due to death) on soft agar plates [1]. There are numerous papers using HIV in cultures and they show beyond the shadow of a doubt that it kills CD4+ cells. In fact, the very first paper by Montagnier et. al specifically mentioned the decline of lymphocytes in the HIV exposed culture but not in the uninfected control cultures [2]. This is consistent with the decline of that cell subset in infected individuals. Also see here [3].

2) Ex vivo evidence:

So that is all fine and dandy, but is this destruction of CD4+ T-cells by HIV also observed in vivo?

Absolutely. Ex vivo studies (those performed in tissue removed from patients or animal models) recapitulated the depletion of T-cells observed in vitro.[4-7].

3) In vivo evidence:

Does in vivo evidence then support in vitro and ex vivo studies? The answer is yes. Numerous animal models have been generated to test anti-HIV strategies. One such model is the Humanized Mouse. Humanized mice are mice which have been transplanted with human immune systems. That is, their immune cells are 100% human. These cells have been taken from human donors and placed in otherwise immune-compromised mice. In some cases the studies have gone as far as to simulate the route of transmission used in humans. For example, rectal exposure of HIV to humanized mice results in infection and a significant decline in CD4+ T-cells [8]. Other animal models show similar patterns. Some of these references are cited here:[9-12].

How Does T-Cell Depletion Occur?

This is the area where there are still some possibilities being researched. New evidence emerges that yields new clues. However, it should be noted that not a single one puts HIV's causality to doubt.

Destruction of CD4+ T-cells has been documented to occur by two general methods; 1) direct cell killing and 2) indirect cell killing.

1) Direct Cell Killing:

Direct cell killing involves the destruction of infected CD4+ cells [13]. This is readily observable in cell cultures and is a method of cell killing utilized by many viruses. Direct cell killing, however, does not appear to contribute as much to T-cell decline as indirect killing.

2) Indirect Cell Killing:

Indirect killing of uninfected cells is likewise supported by a large body of evidence. Isolated HIV proteins can induce apoptosis (programmed cell death) of uninfected cells alone or in combination. For example, the dual expression of gp120 and human CD4 alone is sufficient to cause T-Cell depletion in transgenic mice (despite a lack of infectious HIV) [14]. The protein Tat has likewise been shown to cause uninfected cell death in culture [15]. Apoptosis is observed in uninfected cells as a result of infected cells [16-19] as well as killing of uninfected cells by the host immune system in response to infection [20].

So how can we say with any certainty that the decline in CD4+ T-cells results in the susceptibility to opportunistic infections seen in AIDS patients?

A simple look at other instances of Non-HIV related T-cell decline provides convenient precedents.

Artificially induced CD4+ T-cell depletion due to exposure to monoclonal anti-CD4 antibodies result in immune suppression severe enough to allow for xenografts (tissue grafts from a different species) [21].

Naturally occurring cases include children with Di George's syndrome (an inherited disease which affects, among other things, the production of T-cells) who are highly susceptible to infections. Ataxia telangiectasia, another rare inherited disease, likewise affects the production of T-cells (again, among other things) and results in lowered immunity. Autosomal recessive SCID results in the lack of T-cells and an extreme susceptibility to infections.

Finally, Idiopathic CD4+ T lymphocytopenia (a rare non-HIV related deficit of CD4+ T cells) leads to extreme susceptibility to OIs as seen in advanced AIDS cases [22].

Summary

1. HIV causes depletion of CD4+ T-cells in vitro. This cell-specific depletion is recapitulated ex vivo, and in vivo, both in animal models and in infected humans.
2. Both direct and indirect killing of T-cells has been observed and documented in a) in vitro, b) ex vivo, and c) in vivo both in animal models as well as infected humans.
3. Finally, depletion of T-cells as shown in non-HIV conditions (especially Idiopathic CD4+ T lymphocytopenia) leads to susceptibility to opportunistic infections as seen in advanced AIDS. Thus, there is no logic in saying that HIV-dependent T-cell depletion should be no different.

Again, there are some aspects of HIV biology that still requires elucidation. No scientist will deny this as it is a normal part of science. Rome wasn't built in a day, nor are all aspects of any disease solved instantly. However, all the evidence, past and emerging, supports HIV as the cause of T-cell depletion and thus AIDS.

References

1. The T4 Gene Encodes the AIDS Virus Receptor is Expressed in the Immune System and the Brain. Cell, Vol. 47, 333-348, November 7, 1986.

2. Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS). SCIENCE, VOL. 220 p. 868-870.

3. HIV-1 infection, apoptosis, and CD4 T cell depletion in vitro and in hu-PBL-SCID mice. Int Conf AIDS. 1996 Jul 7-12; 11: 9

4. CXCR4 utilization is sufficient to trigger CD41 T cell depletion in HIV-1-infected human lymphoid tissue. Proc. Natl. Acad. Sci. USA Vol. 96, pp. 663–668, January 1999 Medical Sciences.

5. Dual-tropic (X4R5) HIV-1 preferentially use CCR5 OR CXCR4 in human lymphoid tissue ex vivo: correlation with CD4+ T cell depletion. Int Conf AIDS 2000 Jul 9-14; 13

6. Depletion of CD4 T lymphocytes in human lymphoid tissue infected ex vivo with doxycycline-dependent HIV-1. Virology. 2004 Oct 10;328(1):1-6.

7. CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue. Nature Medicine 5, 344 - 346 (1999)

8. Intrarectal transmission, systemic infection, and CD4+ T cell depletion in humanized mice infected with HIV-1. J Exp Med. 2007 April 16; 204(4): 705–714.

9. HIV-1 infection and CD4+ T cell depletion in the humanized Rag2-/-γc-/- (RAG-hu) mouse model. Retrovirology 2006, 3:76

10. A novel small animal model for HIV-1 infection. The FASEB Journal Vol. 19 July 2005.

11. A Macaque model of HIV-1 Infection. www.pnas.org/cgi/doi/10.1073/pnas.0812587106

12. Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2−/−γc−/− (RAG-hu) mice. Virology Volume 373, Issue 2, 10 April 2008, Pages 342-351

13. HIV-1 Directly Kills CD4+T Cells by a Fas-independent Mechanism. The Journal of Experimental Medicine Volume 187, Number 7, April 6, 1998 1113–1122

14. Induction of CD4' T cell depletion in mice doubly transgenic for HIV gp120 and human CD4. Eur. J. Immunol. 1997.27: 1319-1324

15. Monocytes Treated with Human Immunodeficiency Virus Tat Kill Uninfected CD4+ Cells by a Tumor Necrosis Factor-Related Apoptosis-Induced Ligand-Mediated Mechanism. J Virol. 2003 June; 77(12): 6700–6708.

16. Apoptosis of Bystander T Cells Induced by Human Immunodeficiency Virus Type 1 with Increased Envelope/Receptor Affinity and Coreceptor Binding Site Exposure. Journal of Virology, May 2004, p. 4541-4551, Vol. 78, No. 9

17. Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS. Journal of General Virology (2003), 84, 1649–1661

18. Apoptosis induced in HIV-1-exposed, resting CD4 T cells subsequent to signaling through homing receptors is Fas/Fas ligand-mediated. Journal of Leukocyte Biology Volume 81, January 2007

19. HIV envelope-directed signaling aberrancies and cell death of CD4+ T cells in the absence of TCR co-stimulation. International Immunology, Vol. 8, No 1, pp 65-74

20. HIV-infected humans, but not chimpanzees, have circulating cytotoxic T lymphocytes that lyse uninfected CD4+ cells. J Immunol. 1990 Apr 15;144(8):2992-8.

21. Orthotopic human lung carcinoma xenografts in BALB/c mice immunosuppressed with anti-CD4 monoclonal antibodies and chronic alcohol consumption. Cancer. 2000 Jan 15; 88(2): 468-79

22. Idiopathic CD4+ T-cell lymphocytopenia. Indian Journal of Pediatrics Volume 76, Number 4 / April, 2009

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