Vitamin D and HIV: Letting the Sun Shine In
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IAS–USA Topics in Antiviral Medicine
Perspective
Vitamin D and HIV: Letting the Sun Shine In
Vitamin D is important for cell growth, immunity, and metabolism. Deficiency time spent outdoors, use of protective
has classically been associated with rickets and decreased bone density and clothing, body mass and percentage
more recently with increased risk and severity of autoimmune diseases, of fat (which are inversely related to
cancers, myocardial infarction, diabetes, and infectious diseases. How vitamin D levels), diet (specifically the
vitamin D can affect these diverse conditions is the subject of much research. intake of fish oil, oily fish, and foods
The active form of vitamin D (vitamin D3 ) has been implicated recently with vitamin D supplementation), and
in an intracellular process known as autophagy. In addition to its role in vitamin D supplementation. Persons
maintaining cellular homeostasis during conditions of stress, autophagy with HIV infection frequently have low
plays an important role in the control of many intracellular microorganisms vitamin D levels.3-6 Moreover, patients
including Mycobacterium tuberculosis. Recent work has identified that treated with nonnucleoside reverse
HIV-1 reduces autophagy during permissive infection and that agents that transcriptase inhibitors and protease
induce autophagy, including vitamin D3 , can inhibit HIV-1 replication. These inhibitors are at increased risk of vita-
findings help provide a biological explanation for the increased risk of more min D deficiency.4,7-9 Thus, vitamin D
rapid disease progression observed in HIV-infected persons with low levels deficiency is common in HIV-infected
of vitamin D or with genetic variants within the vitamin D receptor that alter persons regardless of treatment status,
binding to vitamin D. Controlled trials are needed to determine the potential viral load, or CD4+ lymphocyte count.
for therapeutic benefit of vitamin D supplementation in HIV disease. This
article summarizes a presentation by Stephen A. Spector, MD, at the IAS−USA
Vitamin D and Autophagy
continuing medical education program held in Chicago in April 2010.
In 1903, Niels Ryberg Finsen was
awarded a Nobel Prize in Medicine and
Vitamin D is important for cell growth, tes. Evidence indicates that vitamin Physiology in part for showing that
immunity, and metabolism, and vitamin D deficiency is also associated with extensive exposure to sunlight was
D deficiency is common in developed increased risk of HIV infection and dis- frequently effective in treating “lupus
as well as developing countries. Despite ease progression. vulgaris,” (ie, cutaneous tuberculosis
much research, there is still disagree- [TB]). This effect is now known to be
ment as to the optimal level of vitamin associated with the role of vitamin D
Vitamin D Sources
D needed for health. 25-hydroxyvitamin in autophagy, a critical process in cell
D is the metabolite usually measured Lanolin in the skin is converted to death and survival. Under normal con-
in serum, with lower limits of “normal” 7-dehydrocholesterol, which is con- ditions involving infection with many
considered to be between 20 nmol/L verted to pre–vitamin D with exposure intracellular pathogens, the organism
and 38 nmol/L. However, optimal bone to ultraviolet (UV) rays from the sun. is taken into an endosome that joins
health may require levels of at least Pre–vitamin D enters the circulation with an autophagosome in the cyto-
50 nmol/L to 80 nmol/L (20−32 ng/mL) and is metabolized to 25-hydroxyvita- plasm of a macrophage. The autopha-
in adults.1 Vitamin D deficiency is clas- min D, the major circulating form of gosome fuses with a lysosome, acidi-
sically associated with rickets, which the vitamin (which has a circulating fying the autophagosome to form an
still occurs in developed countries half-life of approximately 15 days). It autolysosome; the autolysosome ex-
and remains an important problem in is subsequently converted to the active erts antimicrobial activity and kills the
resource-poor countries, and with de- form, 1,25-dihydroxyvitamin D3 (called microorganism.
creased bone mineral density. It is also vitamin D3), in the kidneys. In addi- In latent Mycobacterium tuberculo-
associated with increased risk and se- tion to exposure to sunlight, vitamin D sis infection, however, the organism
verity of bone diseases, autoimmune sources include natural foods such as impairs the recruitment of hepatocyte
disease, cancer (of the colon, prostate, salmon and other “oily” fish, cod liver growth factor–regulated tyrosine ki-
and breast), myocardial infarction, in- oil, shiitake mushrooms, and egg yolk, nase substrate (Hrs), which plays a cen-
fectious diseases, and possibly diabe- as well as fortified foods and vitamin tral role in late endosome sorting and
supplements (Table 1).2 autophagosomal maturation (Figure
The main factors affecting an indi- 1).10 This effect leads to the inhibition
Dr Spector is distinguished professor of pe-
vidual’s vitamin D status are the extent of autophagy and thus, the retention of
diatrics, chief of the Division of Infectious
Diseases, and director of the Mother-Child- of sunlight exposure, degree of skin live organisms in autophagosomes. Un-
Adolescent HIV Program at the University pigmentation, use of sunscreen (with der such conditions, autophagy in cells
of California San Diego and Rady Children’s sun protection factor [SPF] ≥ 8), lati- can be induced by certain means—
Hospital in San Diego. tude and season of the person’s locale, for example, through cell starvation,
6Vitamin D and HIV Volume 19 Issue 1 February/March 2011
by drugs, and from environmental distinction to apoptosis (which is con- 1,25-dihydroxyvitamin D3 binding to
stress—so that the autophagosome sidered programmed cell death-1, or the vitamin D receptor (VDR), which
containing the bacteria fuses with the PCD-1), although some believe that promotes the formation of the PI3KC3
lysosome, forming the autolysosome once cells are programmed for death, kinase complex and leads to autopha-
and resulting in bacterial killing. autophagy and apoptosis are indis- gosome elongation and subsequent fu-
Autophagy is often referred to as tinguishable. Under conditions of in- sion of the autophagosome with a lyso-
programmed cell death-2 (PCD-2), in fection or other stress, cells proceed some. In the second pathway, after
down one of the PCD binding of 1,25-dihydroxyvitamin D3
pathways. The apop- to the VDR, there is upregulation of
tosis pathway invari- the antimicrobial peptide cathelicidin,
Table 1. Dietary, Supplemental, and Pharmaceutical
ably leads to cell death. resulting in the fusion of autophago-
Sources of Vitamin D2 and Vitamin D3
However, the autopha- somes with lysosomes. The induction
Approximate Vitamin D gy pathway is primarily of autophagy through both pathways
Source
Content involved in processes of ultimately leads to the elimination of
adaptation and survival microorganisms such as Mycobacterium
Natural Sources
through the recycling species.
Salmon of cytoplasmic proteins
Fresh, wild (3.5 oz) 600–1000 IU of vitamin D3 and organelles in an at-
Fresh, farmed (3.5 oz) 100–250 IU of vitamin D3 or D2
Vitamin D and HIV
tempt to promote cell
Canned (3.5 oz) 300–600 IU of vitamin D3 survival and function. There is growing recognition of an as-
Sardines, canned (3.5 oz) 300 IU of vitamin D3 Too much or too little sociation between vitamin D deficien-
autophagy in response cy and the pathogenesis and course of
Mackerel, canned (3.5 oz) 250 IU of vitamin D3 to challenges can result HIV disease. Vitamin D deficiency is
Tuna, canned (3.6 oz) 230 IU of vitamin D3 in cell dysfunction and common in HIV infection. It is present
eventually cell death. in 25% to 75% of infected persons and
Cod liver oil (1 tsp) 400–1000 IU of vitamin D3 In addition to play- has been associated with more rapid
Shiitake mushrooms ing a role in innate im- disease progression. Infants born to
Fresh (3.5 oz) 100 IU of vitamin D2 munity by clearing or HIV-infected women with vitamin D
Sun-dried (3.5 oz) 1600 IU of vitamin D2 destroying intracellular deficiency are at increased risk of in-
Egg yolk 20 IU of vitamin D3 or D2 organisms, autophagy fection and have decreased survival.
is important in adaptive Persons in resource-limited regions
Exposure to sunlight, ultravio- immunity by assisting often have low vitamin D levels. In ad-
let B radiation (0.5 minimal 3000 IU of vitamin D3
erythemal dose)
with major histocom- dition, darkly pigmented skin reduces
patibility complex class the amount of UV light available in
Fortified foods I and II antigen presen- the skin for production of pre–vitamin
Fortified milk 100 IU/8 oz, usually vitamin D3
tation.11,12 Microorgan- D. Numerous studies of black people
isms under the control in the United States and Africa have
Fortified orange juice 100 IU/8 oz vitamin D3 of autophagy include shown an increased risk of vitamin D
Infant formulas 100 IU/8 oz vitamin D3
numerous bacteria, such deficiency, suggesting that insufficient
as M tuberculosis, and levels of vitamin D may be one of sev-
Fortified yogurts 100 IU/8 oz, usually vitamin D3 viruses, including, Dr eral other risk factors contributing to
Fortified butter 50 IU/3.5 oz, usually vitamin D3
Spector and colleagues the severity of HIV disease in persons
believe, HIV-1 (Table 2). living in many developing countries.
Fortified margarine 430 IU/3.5 oz, usually vitamin D3 Vitamin D plays an A number of studies have indicated
Fortified cheeses 100 IU/3 oz, usually vitamin D3
important role in the associations between low vitamin D
killing of microorgan- levels and HIV disease. One such study
Fortified breakfast cereals 100 IU/serving, usually vitamin D3 isms through autopha- performed in white injection drug us-
Supplements
gy.13,14 The induction of ers with HIV infection in Spain showed
autophagy by 1,25-di- that persons with vitamin D receptor
Prescription hydroxyvitamin D3 is variants associated with reduced vita-
Vitamin D2 (ergocalciferol) 50,000 IU/capsule the subject of much min D binding (ie, people homozygous
Drisdol (vitamin D2) liquid investigation. At least 2 for the BB allele) had a statistically
8000 IU/mL
supplements overlapping pathways significant increased risk of progres-
Over the counter appear to be involved sion to AIDS (adjusted hazard ratio
Multivitamin 400 IU vitamin D (D2 or D3) with the induction of [HR], 1.7; P =.036) and were statisti-
Vitamin D3 400, 800, 1000, and 2000 IU autophagy by vitamin cally significantly more likely to have a
Adapted from Holick.2 D. The first involves CD4+ cell count less than 200/µL (HR,
7IAS–USA Topics in Antiviral Medicine
Hydrolyzed Potential Effects sufficient autophagy for cell survival.22
ubiquitin of Vitamin D on Regarding other potential effects
peptides
Nucleus
M tuberculosis HIV-1 Infection of autophagy in HIV disease, Spector
and Zhou hypothesize that toxins pro-
NFκB NFκB The viral products re- duced by HIV replication in microglial
leased by HIV-infected
Autophagosome cells (eg, viral products, neurotoxins,
Lysosome CD4+ lymphocytes and cytokines) cause increased au-
1,25D3 VDR
(eg, gp120) induce tophagic dysfunction and eventually
programmed cell death cell death of neurons, which plays a
of uninfected lympho- role in HIV neurocognitive impair-
cytes. In fact, during ment.23 This premise is supported
Antimicrobial Autophagy acute infection, by- by postmortem findings that brains
activity
stander lymphocytes of patients with HIV encephalopathy
Cathelicidin Autolysosome
are killed more rap- contain higher levels of indicators of
idly than infected autophagy than do those of HIV-sero-
Figure 1. A simplified schematic of a macrophage, showing the cells.18 Although pro- negative persons or HIV-infected per-
role of vitamin D in the killing of microorganisms. 1,25-dihy- grammed cell death sons without HIV encephalopathy.24
droxyvitamin D3 (1,25D3) binds to the vitamin D receptor (VDR) through apoptosis has These findings suggest that aberrant
and through mechanisms not fully identified upregulates the been the mechanism autophagy may be important in the
production of cathelicidin and transcription factors that pro-
most commonly de- pathogenesis of HIV-associated neu-
mote autophagy. In infections with Mycobacterium tuberculo-
sis, an endosome (autophagosome) containing the organism scribed, recent studies rocognitive disorders.
is induced to fuse with a lysosome, leading to acidification of suggest that autopha- It thus appears that HIV controls
the fused autophagosome–lysosome complex (autolysosome), gy may play an impor- autophagy in infected macrophages
resulting in killing of the M tuberculosis organism. Cathelicidin, tant role in bystander and, to some extent, in infected lym-
an antimicrobial peptide, also contributes to mycobacterial kill- CD4+ cell death.19-21 phocytes. That is, the virus, by alter-
ing. NF-kB indicates nuclear factor kB. In contrast to CD4+ ing autophagy within the cells, allows
lymphocytes that are the lymphocyte to survive longer than
2.1; P=.004) than were those with al- killed during HIV-1 infection, infected uninfected bystander cells undergo-
leles Bb or bb, which are associated macrophages are productively infect- ing programmed cell death from viral
with better binding.15 ed by HIV-1 but not killed by the virus. products. Moreover, the drug rapamy-
A recent study in HIV-infected wom- Based on Dr Spector and colleagues' cin, which induces autophagy (via in-
en in Tanzania who gave birth showed recent laboratory findings, it appears hibition of the mammalian target of
a striking relationship between lower that HIV infection of macrophages rapamycin [mTOR] pathway), inhibits
vitamin D levels and increased risk and CD4+ T lymphocytes results in a HIV replication in monocytes.22 Simi-
of HIV disease progression and all- downregulation of autophagy that per- larly, calcitriol, the active form of vitamin
cause mortality (Figure 2).16 Among mits viral replication but also allows D3, can also inhibit viral replication.
infants born to women
with low vitamin D levels
Incidence Rate Ratio of HIV Disease Progression
2.00
in this study, multivariate 1.5
analysis showed a statisti-
to Stage III or IV During Follow-up
Incidence Rate Ratio of All-Cause
1.4 1.75
cally significant increased
Mortality During Follow-up
1.3
risk of HIV transmission 1.50
through breast-feeding 1.2
among children known 1.1 1.25
to be HIV uninfected at
1.0
6 weeks of age (relative 1.00
risk [RR], 2.03; P = .03). 0.9
It also showed a statisti- 0.8 0.75
cally significant increased 0.7
risk of HIV infection at 24 0.50
0.6
months (RR, 1.46; P< .01),
death among live births 0.5 0.25
0 8 16 24 32 40 48 56 64 72 80 0 8 16 24 32 40 48 56 64 72 80
(RR, 1.61; P < .01), over-
all mortality (RR, 1.58; Vitamin D Levels at Baseline (ng/mL) Vitamin D Levels at Baseline (ng/mL)
P < .01), and overall HIV
infection or mortality (RR, Figure 2. Association of vitamin D status with HIV disease progression (left) and all-cause mortality (right) in
1.50; P < .01).17 HIV-infected women in Tanzania. Shaded areas represent confidence intervals. Adapted from Mehta et al.16
8Vitamin D and HIV Volume 19 Issue 1 February/March 2011
Table 2. Microorganisms Under the of decreased bone mineral density in 5. Rodriguez M, Daniels B, Gunawardene S, Rob-
bins GK. High frequency of vitamin D deficien-
Control of Autophagy HIV disease.25 A study of vitamin D cy in ambulatory HIV-positive patients. AIDS
as supplementary treatment for TB Res Hum Retroviruses. 2009;25:9-14.
Bacteria in HIV infection showed no benefit, 6. Van Den Bout-Van Den Beukel CJ, Fievez L, Mi-
chels M, et al. Vitamin D deficiency among HIV
Brucella abortus
although the dose used in the study type 1-infected individuals in the Netherlands:
(100,000 IU of cholecalciferol at base- effects of antiretroviral therapy. AIDS Res Hum
Chlamydia trachomatis line, 5 months, and 8 months) is con- Retroviruses. 2008;24:1375-1382.
Coxiella burnetii 7. Bouvier G. Protease inhibitors can inter-
sidered likely to be too low to provide fere with vitamin D metabolism. HIV Clin.
Legionella pneumophila a therapeutic response.26 2009;21:9-10.
In addition to improved bone 8. Conesa-Botella A, Florence E, Lynen L, Cole-
Listeria monocytogenes bunders R, Menten J, Moreno-Reyes R. De-
health, the potential benefits of vita- crease of vitamin D concentration in patients
Myobacterium tuberculosis min D supplementation in HIV dis- with HIV infection on a non nucleoside reverse
Porphyromonas gingivalis transcriptase inhibitor-containing regimen.
ease may include improved control AIDS Res Ther. 2010;7:40.
Salmonella species of HIV replication, increased CD4+ 9. Welz T, Childs K, Ibrahim F, et al. Efavirenz is
Shigella flexneri
cell count, slower rate of disease pro- associated with severe vitamin D deficiency
and increased alkaline phosphatase. AIDS.
gression, improved control of oppor- 2010;24:1923-1928.
Staphylococcus aureus tunistic infections, decreased risk of 10. Vieira OV, Harrison RE, Scott CC, et al. Acquisi-
Streptococcus pyogenes HIV-related neurocognitive impair- tion of Hrs, an essential component of phago-
somal maturation, is impaired by mycobacte-
ment, and improved overall survival. ria. Mol Cell Biol. 2004;24:4593-4604.
Viruses It remains unclear what the optimal 11. Münz C. Antigen processing via autophagy—
dosage of vitamin D supplementa- not only for MHC class II presentation any-
Coxsackievirus more? Curr Opin Immunol. 2010;22:89-93.
tion might be to provide some level of 12. Schmid D, Münz C. Innate and adaptive immu-
Cytomegalovirus benefit for prevention or treatment of nity through autophagy. Immunity. 2007;27:11-21.
Dengue virus HIV or other infectious diseases. Cur- 13. Levine B, Kroemer G. Autophagy in the patho-
genesis of disease. Cell. 2008;132:27-42.
Herpes simplex virus rent recommended dietary allowances
14. Shin DM, Yuk JM, Lee HM, et al. Mycobacte-
HIV-1
(RDA) of vitamin D are 600 IU for per- rial lipoprotein activates autophagy via TLR2/1/
sons 1 year to 70 years old and 800 IU CD14 and a functional vitamin D receptor sig-
Influenza A virus for individuals older than 70 years. An
nalling. Cell Microbiol. 2010;12:1648-1665.
15. Barber Y, Rubio C, Fernández E, Rubio M,
Poliovirus adult therapeutic dose of cholecalcifer- Fibla J. Host genetic background at CCR5
ol could be as high as 10,000 IU daily. chemokine receptor and vitamin D recep-
Respiratory syncytial virus tor loci and human immunodeficiency virus
Varicella zoster virus
Controlled clinical trials are needed to (HIV) type 1 disease progression among HIV-
determine the optimal dosage of vita- seropositive injection drug users. J Infect Dis.
2001;184:1279-1288.
Parasites min D supplementation and its poten-
16. Mehta S, Giovannucci E, Mugusi FM, et al. Vi-
tial benefits for HIV-infected persons. tamin D status of HIV-infected women and its
Schistosoma haematobium association with HIV disease progression, ane-
Presented by Dr Spector in April 2010. First mia, and mortality. PLoS One. 2010;5:e8770.
draft prepared from transcripts by Matthew 17. Mehta S, Hunter DJ, Mugusi FM, et al. Perina-
Stenger. Reviewed and edited by Dr Spector tal outcomes, including mother-to-child trans-
Controlled trials of vitamin D sup- in March 2011. mission of HIV, and child mortality and their
association with maternal vitamin D status in
plementation have yielded favorable Tanzania. J Infect Dis. 2009;200:1022-1030.
Financial Disclosure: Dr Spector has no rel-
outcomes in patients with bacterial 18. Alimonti JB, Ball TB, Fowke KR. Mechanisms of
evant financial affiliations to disclose. CD4+ T lymphocyte cell death in human im-
infections such as TB (in 3 of 4 stud-
munodeficiency virus infection and AIDS. J Gen
ies) and Helicobacter pylori (in a single Virol. 2003;84:1649-1661.
study); viral upper respiratory tract in- 19. Espert L, Biard-Piechaczyk M. Autophagy in
fection (in 2 of 4 studies) and influenza References HIV-induced T cell death. Curr Top Microbiol
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patients demonstrating immune re- 2007;357:266-281. tophagy and CD4+ T lymphocyte destruction
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combined antiretroviral therapy–naive and creased in postmortem brains of persons with
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9IAS–USA Topics in Antiviral Medicine
25. McComsey GA, Kendall MA, Tebas P, et al. Am J Respir Crit Care Med. 2009;179:843-850.
Alendronate with calcium and vitamin D 27. Institute of Medicine, Food and Nutrition Board.
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treatment of decreased bone mineral density min D. Washington, DC: The National Acad-
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supplementary treatment for tuberculosis: a dou- Top Antivir Med. 2011;19(1):6-10
ble-blind, randomized, placebo-controlled trial. ©2011, IAS–USA
Dermatologic
Manifestations of
HIV Infection in Africa
Resource Card
Cards Available
Based on the Topics in HIV Medicine
article from February/March 2010,
this folding card is available on
request by visiting www.iasusa.org.
Included are brief descriptions of
selected dermatologic manifestations,
along with their differential diagnoses
and treatment options.
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